Polymorphs of dasatinib isopropyl alcohol and process for preparation thereof

ABSTRACT

The invention provides crystalline forms of isopropyl alcohol solvate of dasatinib, methods for their preparation, and pharmaceutical compositions thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims the benefit of the following United StatesProvisional Patent Application Nos. 60/999,998, filed Oct. 23, 2007;61/008,699, filed Dec. 20, 2007; 61/019,106, filed Jan. 4, 2008;61/039,011, filed Mar. 24, 2008; 61/041,384, filed Apr. 1, 2008;61/052,513, filed May 12, 2008; 61/055,309, filed May 22, 2008;61/056,876, filed May 29, 2008; 61/061,054, filed Jun. 12, 2008;61/073,628, filed Jun. 18, 2008; 61/079,548, filed Jul. 10, 2008;61/080,382, filed Jul. 14, 2008; and 61/091,607, filed Aug. 25, 2008.The contents of these applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to polymorphs of dasatinib, process forpreparing said polymorphs, and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

Dasatinib,N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide a compound having the following chemical structure:

also known as BMS-354825, is a drug produced by Bristol-Myers Squibb andsold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ABLand Src family tyrosine kinases inhibitor approved for use in patientswith chronic yelogenous leukemia (CML) after imatinib treatemant andPhiladelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).It is also being assessed for use in metastatic melanoma.

A Preparation of dasatinib is described in U.S. Pat. No. 6,596,746 B1;where the process is done by reacting compound 1 of the followingformula:

with N-(2-hydroxyethyl)piperazine at 80° C. Several crystalline formsare described in the literature, these were designated forms H1-7, BU-2,E2-1, N-6, T1H1-7, and T1E2-1. Crystalline dasatinib monohydrate (H1-7)and butanol solvate (BU-2) along with the processes for theirpreparation are described in WO2005/077945A2. In additionUS2006/0004067A1, which is continuation of WO 2005/077945 A2 alsodescribes two ethanol solvates (E2-1; T1E2-1) and two anhydrous forms(N-6; T1H1-7)

The present invention describes the preparation of new forms ofdasatinib.

Polymorphism, the occurrence of different crystal forms, is a propertyof some compounds and compound complexes. A single compound, likedasatinib, may give rise to a variety of crystalline forms havingdistinct crystal structures and physical characteristics like meltingpoint, x-ray diffraction pattern, infrared absorption fingerprint, andsolid state NMR spectrum. One crystalline form may give rise to thermalbehavior different from that of another crystalline form. Thermalbehavior can be measured in the laboratory by such techniques ascapillary melting point, thermogravimetric analysis (“TGA”), anddifferential scanning calorimetry (“DSC”) as well as content of solventin the crystalline form, which have been used to distinguish polymorphicforms.

The difference in the physical properties of different crystalline formsresults from the orientation and intermolecular interactions of adjacentmolecules or complexes in the bulk solid. Accordingly, polymorphs aredistinct solids sharing the same molecular formula yet having distinctadvantageous physical properties compared to other crystalline forms ofthe same compound or complex.

One of the most important physical properties of pharmaceuticalcompounds is their solubility in aqueous solution, particularly theirsolubility in the gastric juices of a patient. For example, whereabsorption through the gastrointestinal tract is slow, it is oftendesirable for a drug that is unstable to conditions in the patient'sstomach or intestine to dissolve slowly so that it does not accumulatein a deleterious environment. Different crystalline forms or polymorphsof the same pharmaceutical compounds can and reportedly do havedifferent aqueous solubilities.

The discovery of new polymorphic forms and solvates of apharmaceutically useful compound provides a new opportunity to improvethe performance characteristics of a pharmaceutical product. It enlargesthe repertoire of materials that a formulation scientist has availablefor designing, for example, a pharmaceutical dosage form of a drug witha targeted release profile or other desired characteristic. Therefore,there is a need for additional solid state forms of dasatinib.

BRIEF SUMMARY OF THE INVENTION

In one embodiment the present invention encompasses a solvate ofdasatinib selected from the group consisting of: ann-propanol-dimethylsulfoxide (“DMSO”) solvate of dasatinib, a DMSOsolvate of dasatinib, a hemi tetrahydrofuran (“THF”) solvate ofdasatinib, a 2-methyl-tetrahydrofuran (“2-methyl THF”) solvate ofdasatinib, a hemi 1,4-dioxane solvate of dasatinib, a pyridine solvateof dasatinib, a toluene solvate of dasatinib, a methyl isobutyl ketone(“MIBK”) solvate of dasatinib, a mono acetone solvate of dasatinib, aniso-propanol (“IPA”)-DMSO solvate of dasatinib, a 2-butanol-DMSO solvateof dasatinib, an IPA-DMF solvate of dasatinib, an IPA solvate ofdasatinib, an n-propanol-DMF solvate of dasatinib, an n-propanol solvateof dasatinib, a 2-butanol-DMF solvate of dasatinib, a 2-butanol solvateof dasatinib, an n-butanol-DMSO solvate of dasatinib, a DMF-watersolvate of dasatinib, a DMF solvate of dasatinib, a methyl isopropylketone (“MIPK”) solvate of dasatinib, a dimethoxyethane solvate ofdasatinib, a cellosolve solvate of dasatinib, a methylacetate solvate ofdasatinib, a methanol solvate of dasatinib, an ethylacetate solvate ofdasatinib, a 2-pentanole solvate of dasatinib, a dimethyl carbonatesolvate of dasatinib, an isopropylacetate solvate of dasatinib, aethyleneglycol solvate of dasatinib, a dichloromethane solvate ofdasatinib, a methylformate solvate of dasatinib, a tert-butanol solvateof dasatinib, a dimethoxyethane solvate of dasatinib, amethylethylketone (“MEK”) solvate of dasatinib, a monochlorobenzenesolvate of dasatinib, a propylene glycol monoethyl ether (“PGME”)solvate of dasatinib, a glycerol solvate of dasatinib, a cyclopentylmethyl ether solvate of dasatinib, a methyl tert butyl ether (“MTBE”)solvate of dasatinib, an amylalcohol solvate of dasatinib, and aglycerol formal solvate of dasatinib.

In one embodiment, the present invention encompasses an IPA solvate ofdasatinib characterized by data selected from the group consisting of: aPXRD pattern having any 3 peaks selected from the list consisting of:6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 18, asolid-state ¹³C NMR spectrum having signals at about 139.2 and 127.6±0.2ppm; a solid-state ¹³C NMR spectrum having chemical shifts differencesbetween the signal exhibiting the lowest chemical shift and another inthe chemical shift range of 100 to 180 ppm of about 14.2 and 2.6±0.1ppm; a unit cell with parameters as determined by crystal structuredetermination using synchrotron powder diffraction data approximatelyequal to the following:

Cell dimensions: Cell length a 14.9942(5) Å Cell length b 8.45434(22) ÅCell length c 22.6228(16) Å Cell angle alpha 90.0° Cell angle beta95.890(4)° Cell angle gamma 90.0° Cell volume 2852.67(21) Å³ Symmetrycell setting monoclinic Symmetry space group name P 2₁/c,a PXRD pattern and calculated PXRD pattern as depicted in FIG. 96; and acombination thereof. This form can be designated as form A3.

In another embodiment, the present invention encompasses a process forpreparing the IPA solvate of dasatinib characterized by data selectedfrom the group consisting of: a PXRD pattern having any 3 peaks selectedfrom the list consisting of: 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8,21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 18, and combination thereof comprising crystallizingdasatinib from a mixture of IPA and water.

In one embodiment the present invention encompasses an Isopropanol(“IPA”)-DMSO solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe group consisting of: 6.0, 12.0, 15.0, 18.0, 18.3, 18.9, 21.2, 21.5,22.9, 24.1, and 24.6±0.1 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 11, and a combination thereof. The peak positions arecalibrated by means of silicon internal standard.

In another embodiment the present invention encompasses a process forpreparing the iso-propanol (“IPA”)-DMSO solvate of dasatinibcharacterized by data selected from the group consisting of: a PXRDpattern having any 3 peaks selected from the group consisting of: 6.0,12.0, 15.0, 18.0, 18.3, 18.9, 21.2, 21.5, 22.9, 24.1, and 24.6±0.1degrees 2-theta, a powder XRD pattern as depicted in FIG. 11, and acombination thereof comprising crystallizing dasatinib from a mixturecomprising the compound of formula 1, N-(2-hydroxyethyl) piperazine ofthe following formula;

N-ethyldiisopropylamine of the following formula;

and a mixture of DMSO and IPA by reacting compound 1, N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO at a temperature ofabout 76° C. to about 85° C. to obtain a solution comprising dasatinib,and adding IPA to obtain a suspension comprising said crystalline form.

In one embodiment the present invention encompasses an IPA-DMSO solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 6.0, 11.8, 18.2, 20.8, 23.8, 24.3 and 25.5±0.1 degrees 2-theta, apowder XRD pattern as depicted in FIG. 118, a solid-state ¹³C NMRspectrum having signals at about 139.5 and 127.9±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shifts differences betweenthe signal exhibiting the lowest chemical shift and another in thechemical shift range of 100 to 180 ppm of about 14.4 and 2.8±0.1 ppm;and a combination thereof. The peak positions are calibrated by means ofsilicon internal standard.

In another embodiment the present invention encompasses a process forpreparing the IPA-DMSO solvate of dasatinib characterized by dataselected from the group consisting of: a PXRD pattern having peaks atabout 6.0, 20.8 and 24.3±0.1 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 118, and combination thereof comprising crystallizingdasatinib from a mixture comprising the compound 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and a mixture of DMSO and IPA byreacting compound 1, N-(2-hydroxyethyl)piperazine, andN-ethyldiisopropylamine in DMSO at a temperature of about 65° C. toabout 75° C. to obtain a solution comprising dasatinib, and adding IPAto obtain a suspension comprising said crystalline form.

In one embodiment the present invention encompasses an anhydrousdasatinib characterized by data selected from the group consisting of: aPXRD pattern having any 5 peaks selected from the group consisting of:7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8, 22.4, 23.8, 25.3 and 29.1±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 2, and acombination thereof.

In another embodiment the present invention encompasses a process forpreparing the anhydrous dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 5 peaks selected fromthe group consisting of: 7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8, 22.4,23.8, 25.3 and 29.1±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 2, and a combination thereof comprising crystallizingdasatinib from a mixture comprising the compound 1, N-(2-hydroxyethyl)piperazine N-ethyldiisopropylamine, and a mixture of DMSO, methanol andwater.

In another embodiment the present invention encompasses a process forpreparing the anhydrous dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 5 peaks selected fromthe group consisting of: 7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8, 22.4,23.8, 25.3 and 29.1±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 2, and a combination thereof comprising crystallizingdasatinib from a mixture comprising ethanol and water.

In yet another embodiment the present invention encompasses a processfor preparing the anhydrous dasatinib characterized by data selectedfrom the group consisting of: a PXRD pattern having any 5 peaks selectedfrom the group consisting of: 7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8,22.4, 23.8, 25.3 and 29.1±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 2, and a combination thereof comprising providing anopalescent solution of dasatinib in methanol, and precipitating saidcrystalline form to obtain a suspension.

In another embodiment, the present invention encompasses ann-propanol-DMSO solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe group consisting of: 6.0, 11.9, 12.0, 14.9, 17.8, 18.3, 18.7, 21.4,22.9, 24.2 and 24.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 1, and a combination thereof.

In another embodiment the present invention encompasses a DMSO solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the group consistingof: 6.1, 11.8, 15.1, 16.6, 18.2, 19.3, 20.8, 21.6, 23.0, 23.8, 24.3,24.8 and 25.5±0.2 degrees 2-theta, a powder XRD pattern as depicted inFIG. 3, a solid-state ¹³C NMR spectrum having signals at about 139.1 and128.1±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shiftsdifferences between the signal exhibiting the lowest chemical shift andanother in the chemical shift range of 100 to 180 ppm of about 13.9 and2.9±0.1 ppm; and a combination thereof.

In another embodiment the present invention encompasses a THF solvate ofdasatinib characterized by data selected from the group consisting of: aPXRD pattern having any 3 peaks selected from the group consisting of:5.9, 11.8, 12.2, 14.8, 18.3, 18.6, 21.5, 21.8, 24.5, 25.0, and 26.1±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 4, and acombination thereof.

In another embodiment the present invention encompasses a 2-methyl-THFsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the groupconsisting of: 6.0, 11.7, 12.8, 13.2, 17.5, 18.0, 18.4, 20.2, 22.8, 26.3and 27.0±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.5, and a combination thereof.

In another embodiment the present invention encompasses a 1,4-dioxanesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the groupconsisting of: 6.0, 12.0, 14.9, 17.9, 18.2, 18.8, 20.8, 21.2, 22.8, 24.124.1, 24.6 and 25.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 6, and a combination thereof.

In another embodiment the present invention encompasses a pyridinesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the groupconsisting of: 5.9, 11.7, 12.3, 14.0, 18.3, 21.4, 22.0, 22.7, 24.7, and25.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 7,and a combination thereof.

In another embodiment the present invention encompasses a toluenesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the groupconsisting of: 6.0, 12.0, 15.0, 15.4, 16.9, 19.3, 21.3, 21.7, 23.4, 24.1and 24.8±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.8, and a combination thereof.

In another embodiment the present invention encompasses an MIBK solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the group consistingof: 5.8, 10.2, 11.4, 12.5, 17.3, 17.8, 20.0, 21.9, 22.6, 25.8 and26.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 9,and a combination thereof.

In another embodiment the present invention encompasses a mono acetonesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the groupconsisting of: 5.9, 11.7, 12.3, 14.7, 17.6, 18.5, 21.4, 22.1, 22.8, 24.7and 25.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.10, and a combination thereof.

In another embodiment the present invention encompasses a 2-butanol-DMSOsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the groupconsisting of: 6.0, 12.0, 14.9, 17.9, 18.2, 18.9, 21.1, 22.8, 24.0,24.5, 25.6 and 26.1±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 12, and a combination thereof.

The present invention encompasses an amorphous dasatinib.

The present invention encompasses an amorphous dasatinib characterizedby data selected from the group consisting of: a powder XRD pattern asdepicted in FIG. 16, a powder XRD pattern as depicted in FIG. 99, and acombination thereof.

In another embodiment, the present invention encompasses an IPA-DMFsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.0, 14.9, 17.8, 18.2, 18.7, 21.4, 22.8, 24.2and 24.7±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.17, and a combination thereof.

In another embodiment, the present invention encompasses ann-propanol-DMF solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.9, 11.8, 12.2, 14.9, 17.7, 18.3, 18.6, 21.4,21.7, 24.4 and 24.9±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 19, and a combination thereof.

In another embodiment, the present invention encompasses an n-propanolsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.1, 14.9, 17.8, 18.3, 18.7, 21.5, 21.6,22.8, 24.3 and 24.8±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 20, and a combination thereof.

In another embodiment, the present invention encompasses a 2-butanol-DMFsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.7, 12.0, 14.7, 17.6, 18.1, 18.6, 21.4, 22.6,24.1, 24.6 and 25.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 21, and a combination thereof.

In one embodiment, the present invention encompasses a 2-butanol solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the list consistingof: 5.9, 11.8, 12.0, 14.7, 17.7, 18.1, 18.7, 21.3, 22.6, 24.1 and24.6±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 22,and a combination thereof.

In another embodiment, the present invention encompasses an-butanol-DMSO solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.9, 11.9, 12.0, 14.8, 17.8, 18.2, 18.7, 21.3,22.7, 24.1 and 24.6±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 23, and a combination thereof.

In another embodiment, the present invention encompasses a DMF-watersolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.4, 10.8, 12.1, 14.8, 16.4, 21.4, 22.1, 24.2, 24.8 and25.4±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 24,and a combination thereof.

In another embodiment, the present invention encompasses a DMF solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the list consistingof: 5.8, 11.5, 12.3, 14.6, 17.3, 18.2, 21.2, 22.1, 22.6, 24.7 and25.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 25,and a combination thereof.

In another embodiment, the present invention encompasses a MIPK solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the list consistingof: 5.7, 12.0, 14.6, 18.0, 18.2, 22.4 and 24.6±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 26, and a combination thereof.

In another embodiment, the present invention encompasses adimethoxyethane solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.7, 6.0, 11.4, 16.8, 19.7 and 24.1±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 27, and a combinationthereof.

In another embodiment, the present invention encompasses a cellosolvesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.5, 11.1, 11.6, 15.7, 16.8 and 23.4±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 28, and a combination thereof.

In another embodiment, the present invention encompasses a methylacetatesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.1, 14.8, 17.7, 18.2 and 21.6±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 29, and a combinationthereof.

In another embodiment, the present invention encompasses a methanolsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 7.1, 11.9, 12.7, 14.3, 16.0, 19.1 and 21.6±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 30, and a combinationthereof.

In another embodiment, the present invention encompasses an ethylacetatesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 8.9, 11.8, 12.4, 16.1, 22.3 and 25.4±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 31, and a combinationthereof.

In another embodiment, the present invention encompasses a 2-pentanolesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.6, 11.3, 17.1, 17.3 and 21.9±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 32, and a combination thereof.

In another embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib characterized by data selected from thegroup consisting of: PXRD pattern having any 3 peaks selected from thelist consisting of: 12.1, 17.3, 18.3, 24.5, 24.7 and 26.5±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 33, and a combinationthereof.

In another embodiment, the present invention encompasses anisopropylacetate solvate of dasatinib characterized by data selectedfrom the group consisting of: PXRD pattern having any 3 peaks selectedfrom the list consisting of: 5.8, 10.3, 12.3, 17.3, 21.9 and 24.4±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 34, and acombination thereof.

In another embodiment, the present invention encompasses adichloromethane solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.9, 7.1, 11.8, 14.4, 14.8, 18.3 and 22.9±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 36, and acombination thereof.

In another embodiment, the present invention encompasses a methylformatesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 7.1, 11.9, 14.3, 16.0, 24.2 and 25.1±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 37, and a combinationthereof.

In another embodiment, the present invention encompasses a tert-butanolsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.0, 15.0, 17.7, 18.1 and 26.3±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 38, and a combinationthereof.

In another embodiment, the present invention encompasses adimethoxyethane solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 6.1, 12.1, 15.3, 21.0, 23.1 and 24.4±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 39, and a combinationthereof.

In another embodiment, the present invention encompasses a MEK solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the list consistingof: 5.9, 12.2, 14.7, 15.1, 21.7, 24.5 and 24.9±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 40, and a combination thereof.

In another embodiment, the present invention encompasses amonochlorobenzene solvate of dasatinib characterized by data selectedfrom the group consisting of: PXRD pattern having any 3 peaks selectedfrom the list consisting of: 6.2, 12.4, 15.8, 18.7, 23.6 and 26.8±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 41, and acombination thereof.

In another embodiment, the present invention encompasses a PGME solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the list consistingof: 5.7, 11.5, 17.0, 17.4, 22.0, 23.1 and 24.3±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 42, and a combination thereof.

In another embodiment, the present invention encompasses a cyclopentylmethyl ether solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.8, 14.6, 17.5, 21.1, 22.4, 23.9 and 24.3±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 44, and acombination thereof.

In another embodiment, the present invention encompasses a MTBE solvateof dasatinib characterized by data selected from the group consistingof: PXRD pattern having any 3 peaks selected from the list consistingof: 5.8, 10.0, 19.2, 19.6, 22.4, 25.7 and 26.1±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 45, and a combination thereof.

In another embodiment, the present invention encompasses an amylalcoholsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.6, 10.4, 11.2, 21.7, 23.1 and 26.1±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 46, and a combination thereof.

In one embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib characterized by data selected from thegroup consisting of: PXRD pattern having any 3 peaks selected from thelist consisting of: 12.5, 13.6, 16.2, 21.7 and 25.6±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 47, and a combination thereof.

In one embodiment, the present invention encompasses an ethylene glycolsolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 7.5, 12.3, 14.7 and 16.4±0.2 degrees 2-theta, a powderXRD pattern as depicted in FIG. 48, and a combination thereof.

In one embodiment, the present invention encompasses an anhydrous formof dasatinib characterized by data selected from the group consistingof: PXRD pattern having peaks at about 5.1 and 10.2±0.2 degrees 2-thetaand any 3 peaks selected from the list consisting of: 6.0, 20.3, 20.5,23.5 and 26.8±0.2 degrees 2-theta, a powder XRD pattern as depicted inFIG. 97, and a combination thereof.

In one embodiment, the present invention encompasses a monochlorobenzenesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 12.0, 15.3, 17.9, 24.3 and 26.2±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 98, and a combination thereof.

In one embodiment, the present invention encompasses dimethyl carbonatesolvate of dasatinib characterized by data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from a listconsisting of: 12.0, 16.7, 19.1, 21.0, 21.6, 23.0 and 24.5±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 109, and a combinationthereof.

In one embodiment, the present invention encompasses a methyl isopropylketone (“MIPK”) solvate of dasatinib characterized by data selected fromthe group consisting of: PXRD pattern having any 3 peaks selected fromthe list consisting of: 10.1, 12.1, 12.7, 17.5, 17.9, 19.9 and 25.9±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 110, and acombination thereof.

In one embodiment, the present invention encompasses a monochlorobenzenesolvate of dasatinib characterized by a data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.6, 10.3, 11.3, 17.3, 22.3 and 26.1±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 111, and a combination thereof.

In one embodiment, the present invention encompasses a glycerol formalsolvate of dasatinib characterized by a data selected from the groupconsisting of: PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 17.8, 18.6, 20.5, 23.8 and 24.3±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 125, and a combinationthereof.

In one embodiment, the present invention encompasses a crystalline formof dasatinib characterized by data selected from the group consistingof: PXRD pattern having peaks at about 6.4 and 14.0±0.2 degrees 2-thetaand any 3 peaks selected from the list consisting of: 6.4, 12.7, 14.0,19.0, 21.7 and 25.0±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 131, and a combination thereof.

In yet another embodiment, the invention encompasses a pharmaceuticalcomposition comprising at least one of the above-described polymorphs ofdasatinib, and at least one pharmaceutically acceptable excipient.

In one embodiment, the present invention also encompasses apharmaceutical composition comprising at least one of the abovedescribed polymorphs of dasatinib prepared according to the processes ofthe present invention, and at least one pharmaceutically acceptableexcipient.

In another embodiment, the invention encompasses a process for preparinga pharmaceutical composition comprising at least one of the abovepolymorphs of dasatinib, and at least one pharmaceutically acceptableexcipient.

In another embodiment, the invention encompasses a method of treatingchronic yelogenous leukemia after imatinib treatemant, and Philadelphiachromosome-positive acute lymphoblastic leukemia comprisingadministering a pharmaceutical composition comprising at least one ofthe above polymorphs of dasatinib to a patient in need thereof.

One embodiment of the invention provides the use of the abovecrystalline forms of dasatinib of the present invention for themanufacture of a pharmaceutical composition.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a powder XRD pattern of crystalline dasatinib form K2.

FIG. 2 shows a powder XRD pattern of crystalline dasatinib form B.

FIG. 3 shows a powder XRD pattern of crystalline dasatinib form C.

FIG. 4 shows a powder XRD pattern of crystalline dasatinib form D.

FIG. 5 shows a powder XRD pattern of crystalline dasatinib form E.

FIG. 6 shows a powder XRD pattern of crystalline dasatinib form F.

FIG. 7 shows a powder XRD pattern of crystalline dasatinib form G.

FIG. 8 shows a powder XRD pattern of crystalline dasatinib form H.

FIG. 9 shows a powder XRD pattern of crystalline dasatinib form I.

FIG. 10 shows a powder XRD pattern of crystalline dasatinib form J.

FIG. 11 shows a powder XRD pattern of crystalline dasatinib form A2.

FIG. 12 shows a powder XRD pattern of crystalline dasatinib form L2.

FIG. 13 shows a powder XRD pattern of crystalline dasatinib form G andM.

FIG. 14 shows a powder XRD pattern of Dasatinib form H1-7 (monohydrate)obtained in example 21.

FIG. 15 shows a powder XRD pattern of Dasatinib form T1E2-1(hemi-ethanolate) obtained in examples 24 and 25.

FIG. 16 shows a powder XRD pattern of amorphous Dasatinib.

FIG. 17 shows a powder XRD pattern of crystalline dasatinib form A1.

FIG. 18 shows a powder XRD pattern of crystalline dasatinib form A3.

FIG. 19 shows a powder XRD pattern of crystalline dasatinib form K1

FIG. 20 shows a powder XRD pattern of crystalline dasatinib form K3

FIG. 21 shows a powder XRD pattern of crystalline dasatinib form L1

FIG. 22 shows a powder XRD pattern of crystalline dasatinib form L3

FIG. 23 shows a powder XRD pattern of crystalline dasatinib form N2

FIG. 24 shows a powder XRD pattern of crystalline dasatinib form P

FIG. 25 shows a powder XRD pattern of crystalline dasatinib form Q

FIG. 26 shows a powder XRD pattern of crystalline dasatinib form AA

FIG. 27 shows a powder XRD pattern of crystalline dasatinib form AB

FIG. 28 shows a powder XRD pattern of crystalline dasatinib form AC

FIG. 29 shows a powder XRD pattern of crystalline dasatinib form AD

FIG. 30 shows a powder XRD pattern of crystalline dasatinib form AE

FIG. 31 shows a powder XRD pattern of crystalline dasatinib form AF

FIG. 32 shows a powder XRD pattern of crystalline dasatinib form AG

FIG. 33 shows a powder XRD pattern of crystalline dasatinib form AI

FIG. 34 shows a powder XRD pattern of crystalline dasatinib form AJ

FIG. 35 shows a powder XRD pattern of amorphous dasatinib.

FIG. 36 shows a powder XRD pattern of crystalline dasatinib form AL

FIG. 37 shows a powder XRD pattern of crystalline dasatinib form AM

FIG. 38 shows a powder XRD pattern of crystalline dasatinib form AN

FIG. 39 shows a powder XRD pattern of crystalline dasatinib form AP

FIG. 40 shows a powder XRD pattern of crystalline dasatinib form AQ

FIG. 41 shows a powder XRD pattern of crystalline dasatinib form AR

FIG. 42 shows a powder XRD pattern of crystalline dasatinib form AS

FIG. 43 shows a powder XRD pattern of amorphous dasatinib.

FIG. 44 shows a powder XRD pattern of crystalline dasatinib form AU

FIG. 45 shows a powder XRD pattern of crystalline dasatinib form AV

FIG. 46 shows a powder XRD pattern of crystalline dasatinib form AH

FIG. 47 shows a powder XRD pattern of crystalline dasatinib form AY

FIG. 48 shows a powder XRD pattern of crystalline dasatinib form AW

FIG. 49 shows a TGA thermogram of crystalline Dasatinib form AA

FIG. 50 shows a DSC thermogram of crystalline Dasatinib form AA

FIG. 51 shows a TGA thermogram of crystalline Dasatinib form AB

FIG. 52 shows a DSC thermogram of crystalline Dasatinib form AB

FIG. 53 shows a TGA thermogram of crystalline Dasatinib form AC

FIG. 54 shows a DSC thermogram of crystalline Dasatinib form AC

FIG. 55 shows a TGA thermogram of crystalline Dasatinib form AD

FIG. 56 shows a DSC thermogram of crystalline Dasatinib form AD

FIG. 57 shows a TGA thermogram of crystalline Dasatinib form AE

FIG. 58 shows a TGA thermogram of crystalline Dasatinib form AF

FIG. 59 shows a DSC thermogram of crystalline Dasatinib form AF

FIG. 60 shows a TGA thermogram of crystalline Dasatinib form AG

FIG. 61 shows a DSC thermogram of crystalline Dasatinib form AG

FIG. 62 shows a TGA thermogram of crystalline Dasatinib form AI

FIG. 63 shows a DSC thermogram of crystalline Dasatinib form AI

FIG. 64 shows a TGA thermogram of crystalline Dasatinib form AJ

FIG. 65 shows a DSC thermogram of crystalline Dasatinib form AJ

FIG. 66 shows a TGA thermogram of crystalline Dasatinib form AK

FIG. 67 shows a DSC thermogram of crystalline Dasatinib form AK

FIG. 68 shows a TGA thermogram of crystalline Dasatinib form AL

FIG. 69 shows a DSC thermogram of crystalline Dasatinib form AL

FIG. 70 shows a TGA thermogram of crystalline Dasatinib form AM

FIG. 71 shows a DSC thermogram of crystalline Dasatinib form AM

FIG. 72 shows a TGA thermogram of crystalline Dasatinib form AN

FIG. 73 shows a DSC thermogram of crystalline Dasatinib form AN

FIG. 74 shows a TGA thermogram of crystalline Dasatinib form AP

FIG. 75 shows a DSC thermogram of crystalline Dasatinib form AP

FIG. 76 shows a TGA thermogram of crystalline Dasatinib form AQ

FIG. 77 shows a DSC thermogram of crystalline Dasatinib form AQ

FIG. 78 shows a TGA thermogram of crystalline Dasatinib form AR

FIG. 79 shows a DSC thermogram of crystalline Dasatinib form AR

FIG. 80 shows a TGA thermogram of crystalline Dasatinib form AS

FIG. 81 shows a DSC thermogram of crystalline Dasatinib form AS

FIG. 82 shows a TGA thermogram of crystalline Dasatinib form AT

FIG. 83 shows a DSC thermogram of crystalline Dasatinib form AT

FIG. 84 shows a TGA thermogram of crystalline Dasatinib form AU

FIG. 85 shows a DSC thermogram of crystalline Dasatinib form AU

FIG. 86 shows a TGA thermogram of crystalline Dasatinib form AV

FIG. 87 shows a DSC thermogram of crystalline Dasatinib form AV

FIG. 88 shows a TGA thermogram of crystalline Dasatinib form AW

FIG. 89 shows a DSC thermogram of crystalline Dasatinib form AW

FIG. 90 shows a TGA thermogram of crystalline Dasatinib form AY

FIG. 91 shows a DSC thermogram of crystalline Dasatinib form AY

FIG. 92 shows a TGA thermogram of crystalline Dasatinib amorphous

FIG. 93 shows a DSC thermogram of crystalline Dasatinib amorphous

FIG. 94 shows a TGA thermogram of crystalline Dasatinib form AH

FIG. 95 shows a TGA thermogram of crystalline Dasatinib form AH

FIG. 96 shows comparison of calculated and observed XRPD diffractogramof crystalline Dasatinib IPA solvate (Form A3).

FIG. 97 shows a powder XRD pattern of crystalline dasatinib form BA

FIG. 98 shows a powder XRD pattern of crystalline dasatinib form BB

FIG. 99 shows a powder XRD pattern of amorphous dasatinib.

FIG. 100 shows a TGA thermogram of crystalline Dasatinib form BA

FIG. 101 shows a DSC thermogram of crystalline Dasatinib form BA

FIG. 102 shows a TGA thermogram of crystalline Dasatinib form BB

FIG. 103 shows a DSC thermogram of crystalline Dasatinib form BB

FIG. 104 shows a TGA thermogram of crystalline Dasatinib form BC

FIG. 105 shows a DSC thermogram of crystalline Dasatinib form BC

FIG. 106 shows a PXRD pattern of pure crystalline Dasatinib form T1E2-1as obtained in examples 64-71

FIG. 107 shows a PXRD pattern of wet crystalline Dasatinib form AJ

FIG. 108 shows a PXRD pattern of wet crystalline Dasatinib form AL

FIG. 109 shows a PXRD pattern of crystalline Dasatinib form BD

FIG. 110 shows a PXRD pattern of crystalline Dasatinib form BG

FIG. 111 shows a PXRD pattern of crystalline Dasatinib form BJ

FIG. 112 shows a TGA thermogram of crystalline Dasatinib form BD

FIG. 113 shows a DSC thermogram of crystalline Dasatinib form BD

FIG. 114 shows a TGA thermogram of crystalline Dasatinib form BG

FIG. 115 shows a DSC thermogram of crystalline Dasatinib form BG

FIG. 116 shows a TGA thermogram of crystalline Dasatinib form BJ

FIG. 117 shows a DSC thermogram of crystalline Dasatinib form BJ

FIG. 118 shows a powder XRD pattern of crystalline dasatinib form A21

FIG. 119 shows a full-width solid state ¹³C NMR spectrum of crystallinedasatinib form C

FIG. 120 shows a detailed solid state ¹³C NMR spectrum of crystallinedasatinib form C

FIG. 121 shows a full-width solid state ¹³C NMR spectrum of crystallinedasatinib form A3

FIG. 122 shows a detailed solid state ¹³C NMR spectrum of crystallinedasatinib form A3

FIG. 123 shows a full-width solid state ¹³C NMR spectrum of crystallinedasatinib form A21

FIG. 124 shows a detailed solid state ¹³C NMR spectrum of crystallinedasatinib form A21

FIG. 125 shows a powder XRD pattern of crystalline dasatinib form BL

FIG. 126 shows a TGA thermogram of crystalline dasatinib form BL

FIG. 127 shows a DSC thermogram of crystalline dasatinib form BL

FIG. 128 shows a microscope image of crystalline dasatinib form A3

FIG. 129 shows a microscope image of crystalline dasatinib form A21

FIG. 130 shows a powder XRD pattern of crystalline Dasatinib form N-6(anhydrous).

FIG. 131 shows a powder XRD pattern of crystalline Dasatinib form BM.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to polymorphs of dasatinib, process forpreparing said polymorphs, and pharmaceutical compositions thereof.

As used herein, the term “Room temperature” refers to a temperaturebetween about 20° C. and about 30° C., preferably about 25° C.

As used herein, the term “Overnight” refers to a period of between about11 and about 13 hours, preferably about 12 hours.

As used herein, unless otherwise defined, the term “N-6” when referringto crystalline form of dasatinib means any hydrous form of dasatinibthat exhibits an X-ray powder diffraction pattern having characteristicpeaks expressed in degrees 2-theta at approximately 6.9, 12.4, 13.2,13.8, 16.8, 17.2, 21.1, 24.4, 24.9 and 27.8±0.2 degrees 2-theta.

As used herein, unless otherwise defined, the term “H1-7” when referringto crystalline form of dasatinib means monohydrate form of dasatinibthat exhibits an X-ray powder diffraction pattern having characteristicpeaks expressed in degrees 2-theta at approximately 4.6, 9.2, 11.2,13.8, 15.2, 17.9, 19.5, 23.1, 23.6, 25.9 and 28.0±0.2 degrees 2-theta.

As used herein, unless otherwise defined, the term “BU-2” when referringto crystalline form of dasatinib means solvate of dasatinib thatexhibits an X-ray powder diffraction pattern having characteristic peaksexpressed in degrees 2-theta at approximately 5.9, 11.7, 12.0, 14.7,17.6, 18.1, 18.6, 21.3, 24.1 and 24.6±0.2 degrees 2-theta.

As used herein, unless otherwise defined, the term “T1E2-1” meanssolvate of dasatinib that exhibits an X-ray powder diffraction patternhaving characteristic peaks expressed in degrees 2-theta atapproximately 7.2, 11.9, 14.3, 16.0, 18.7, 19.1, 20.7, 21.5, 24.2 and25.0±0.2 degrees 2-theta.

As used herein, the term “glycerol formal solvate” refers to a mixtureof 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane (60:40), bothof which are cyclic ether compounds having 2 oxygen atoms in the ringstructure and substituted by alcohol group.

In one embodiment the present invention encompasses a solvate ofdasatinib selected from the group consisting of: an-propanol-dimethylsulfoxide (“DMSO”) solvate of dasatinib, a DMSOsolvate of dasatinib, a hemi tetrahydrofuran (“THF”) solvate ofdasatinib, a 2-methyl-tetrahydrofuran (“2-methyl THF”) solvate ofdasatinib, a hemi 1,4-dioxane solvate of dasatinib, a pyridine solvateof dasatinib, a toluene solvate of dasatinib, a methyl isobutyl ketone(“MIBK”) solvate of dasatinib, a mono acetone solvate of dasatinib, aniso-propanol (“IPA”)-DMSO solvate of dasatinib, a 2-butanol-DMSO solvateof dasatinib, an IPA-DMF solvate of dasatinib, an IPA solvate ofdasatinib, an n-propanol-DMF solvate of dasatinib, an n-propanol solvateof dasatinib, a 2-butanol-DMF solvate of dasatinib, a 2-butanol solvateof dasatinib, an n-butanol-DMSO solvate of dasatinib, a DMF-watersolvate of dasatinib, a DMF solvate of dasatinib, a methyl isopropylketone (“MIPK”) solvate of dasatinib, a dimethoxyethane solvate ofdasatinib, a cellosolve solvate of dasatinib, a methylacetate solvate ofdasatinib, a methanol solvate of dasatinib, an ethylacetate solvate ofdasatinib, a 2-pentanole solvate of dasatinib, a dimethyl carbonatesolvate of dasatinib, an isopropylacetate solvate of dasatinib, aethyleneglycol solvate of dasatinib, a dichloromethane solvate ofdasatinib, a methylformate solvate of dasatinib, a tert-butanol solvateof dasatinib, a dimethoxyethane solvate of dasatinib, amethylethylketone (“MEK”) solvate of dasatinib, a monochlorobenzenesolvate of dasatinib, a propylene glycol monoethyl ether (“PGME”)solvate of dasatinib, a glycerol solvate of dasatinib, a cyclopentylmethyl ether solvate of dasatinib, a methyl tert butyl ether (“MTBE”)solvate of dasatinib, an amylalcohol solvate of dasatinib, and aglycerol formal solvate of dasatinib.

In another embodiment, the present invention encompasses an IPA solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and24.7±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 18, asolid-state ¹³C NMR spectrum having signals at about 139.2 and 127.6±0.2ppm; a solid-state ¹³C NMR spectrum having chemical shifts differencesbetween the signal exhibiting the lowest chemical shift at 125±1.0 ppmand another in the chemical shift range of 100 to 180 ppm of about 14.2and 2.6±0.1 ppm; a unit cell with parameters as determined by crystalstructure determination using synchrotron powder diffraction dataapproximately equal to the following:

Cell dimensions: Cell length a 14.9942(5) Å Cell length b 8.45434(22) ÅCell length c 22.6228(16) Å Cell angle alpha 90.0° Cell angle beta95.890(4)° Cell angle gamma 90.0° Cell volume 2852.67(21) Å³ Symmetrycell setting monoclinic Symmetry space group name P 2₁/ca PXRD pattern and calculated PXRD pattern as depicted in FIG. 96, and acombination thereof. The signal exhibiting the lowest chemical shift inthe chemical shift range of 100 to 180 ppm is typically at about 125±1ppm. This form can be designated as form A3.

In a preferred embodiment, the present invention encompasses an IPAsolvate of dasatinib designated Form A3, characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 6.0, 11.9,12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees2-theta.

The IPA solvate of dasatinib can also be characterized by a PXRD patternhaving peaks at about 6.0 and 17.9±0.2 degrees 2-theta and any 3 peaksat positions selected from the group consisting of: 11.9, 14.9, 21.4,24.2 and 24.7±0.2 degrees 2-theta. The peak positions are calibrated bymeans of silicon internal standard.

The above IPA solvate of dasatinib designated Form A3 can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 6.0, 11.9, 12.0, 14.9, 17.9 and 18.3±0.2degrees 2-theta; a powder XRD pattern with peaks at about 11.9, 12.0,21.4, 22.9 and 24.7±0.2 degrees 2-theta; a content of IPA of about 9% toabout 13% by weight, as measured by GC. Preferably, the IPA content isabout 10% to 12% by weight as measured by GC. Theoretical content of IPAin an IPA solvate is typically about 11% by weight.

In addition, crystalline Dasatinib Form A3 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7 orany other form.

Typically, the amount of form N-6 in form A3 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8 and 16.8 deg±0.2 degrees 2-theta and the amount of form H1-7 inform A3 is measured by PXRD using any peaks selected from the groupconsisting of peaks at: 4.6, 9.2, 11.2, 15.2 and 19.5 deg±0.2 degrees2-theta.

The advantage of form A3 is a size and shape of crystals that allowseasier processing such as filtration or pouring of a bulk material. Thecrystals are of size of about 50 μm to about 300 μm having typically aplate shape. Typical crystals are depicted in FIG. 128.

Form A3 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture of IPA and water.

The crystallization comprises providing a solution of dasatinib in amixture of IPA and water, and precipitating said crystalline form toobtain a suspension.

Preferably, the solution is provided by combining dasatinib, IPA andwater, and heating the combination. Preferably, heating is to aboutreflux temperature.

Preferably, precipitation is obtained by cooling the solution.Preferably, cooling is to a temperature of about 20° C. to about 0° C.,more preferably, for about 5° C. to about 0° C.

The process for preparing form A3 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

In another embodiment the present invention encompasses an IPA-DMSOsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 12.0, 15.0, 18.0, 18.3, 18.9, 21.2, 21.5, 22.9,24.1, and 24.6±0.1 degrees 2-theta, a powder XRD pattern as depicted inFIG. 11, and combination thereof. The peak positions are calibrated bymeans of silicon internal standard. This form can be designated as formA2.

In a preferred embodiment the present invention encompasses an IPA-DMSOsolvate of dasatinib designated Form A2 characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 6.0, 12.0,15.0, 18.0, 18.3, 18.9, 21.2, 21.5, 22.9, 24.1, and 24.6±0.1 degrees2-theta.

The above IPA-DMSO solvate of dasatinib designated Form A2 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 12.0, 15.0, 21.2, and24.6±0.1 degrees 2-theta, a content of IPA of about 6-9% by weight asmeasured by GC, and a content of DMSO of about 3-5% by weight asmeasured by GC.

In addition, crystalline Dasatinib Form A2 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form A2 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8 and 16.8 deg±0.1 degrees 2-theta.

Form A2 can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound 1 of the following formula

N-(2-hydroxyethyl) piperazine of the following formula;

N-ethyldiisopropylamine of the following formula;

and a mixture of DMSO and IPA by reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO at atemperature of about 76° C. to about 85° C. to obtain a solutioncomprising dasatinib, and adding IPA to obtain a suspension comprisingsaid crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 76° C. to about 85° C., more preferably,at a temperature of about 80° C. to about 85° C., most preferably, atabout 80° C. Preferably, the reaction is done upon stirring. Preferably,stirring is done for about 1 hour to about 2 hours.

Preferably, IPA is added at a temperature of about 80° C., providing thesuspension. Typically, the suspension is cooled to increase the yield ofthe precipitated crystalline form. Preferably, cooling is to about roomtemperature to about 0° C., more preferably, to about 20° C. to about10° C.

The process for preparing form A2 of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses an IPA-DMSOsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks at positions selectedfrom the group consisting of: 6.0, 11.8, 18.2, 20.8, 23.8, 24.3 and25.5±0.1 degrees 2-theta, a powder XRD pattern as depicted in FIG. 118,a solid-state ¹³C NMR spectrum having signals at about 139.5 and127.9±0.2 ppm; and a solid-state ¹³C NMR spectrum having chemical shiftsdifferences between the signal exhibiting the lowest chemical shift at125±1.0 ppm and another in the chemical shift range of 100 to 180 ppm ofabout 14.4 and 2.8±0.1 ppm; and combination thereof. The signalexhibiting the lowest chemical shift in the chemical shift range of 100to 180 ppm is typically at about 125±1 ppm. The peak positions arecalibrated by means of silicon internal standard. This form can bedesignated as form A21.

In a preferred embodiment the present invention encompasses an IPA-DMSOsolvate of dasatinib designated Form A21 characterized by a PXRD patternhaving peaks at about 6.0 and 20.8±0.1 degrees 2-theta and any 3 peaksat positions selected from the group consisting of: 11.8, 18.2, 23.8,24.3 and 25.5±0.2 degrees 2-theta

The above IPA-DMSO solvate of dasatinib designated Form A21 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 20.8, 23.9, 24.3 and25.5±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.9,18.2, 20.8, 23.9 and 24.3±0.2 degrees 2-theta; a content of IPA of about5-7% by weight as measured by GC, and a content of DMSO of about 5-7% byweight as measured by GC.

In addition, crystalline Dasatinib Form A21 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7 orany other form.

Typically, the amount of form N-6 in form A21 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2 and16.8 deg±0.2 degrees 2-theta and the amount of form H1-7 in form A21 ismeasured by PXRD using any peaks selected from the group consisting ofpeaks at: 4.6, 9.2, 11.2, 15.2 and 19.5 deg±0.2 degrees 2-theta.

The advantage of form A21 is the size and shape of its crystals thatallows easier processing such as filtration or pouring of a bulkmaterial. The crystals are of size of about 50 μm to about 200 μm havingtypically an oblong plate shape. Typical crystals of form A21 aredepicted in FIG. 129.

Form A21 can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound 1, N-(2-hydroxyethyl) piperazine,N-ethyldiisopropylamine and a mixture of DMSO and IPA by reactingcompound 1, N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine inDMSO at a temperature of about 65° C. to about 75° C. to obtain asolution comprising dasatinib, and adding IPA to obtain a suspensioncomprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 65° C. to about 75° C., more preferably,at about 70° C. Preferably, the reaction is done upon stirring.Preferably, stirring is done for about 3 hours.

Preferably, IPA is added at a temperature of about 70° C. to about 75°C., more preferably at about 70° C., providing the suspension.Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, cooling is to about roomtemperature to about 0° C., more preferably, to about 20° C. to about10° C.

Preferably, the suspension is stirred prior to the recovery step.Preferably, stirring is for about 0.5 hours to about 2 hours, preferablyabout 1 hour.

The process for preparing form A21 of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In one embodiment, the present invention encompasses an anhydrous formof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 5 peaks selected from the list consistingof: 7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8, 22.4, 23.8, 25.3 and29.1±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 2,and combination thereof. This form can be designated as form B.

The above form B of dasatinib can be also characterized by a PXRDpattern having peaks at about 7.2 and 14.4±0.2 degrees 2-theta and any 3peaks at positions selected from the group consisting of: 11.9, 16.5,17.3, 19.1, 22.4 and 25.3±0.2 degrees 2-theta. The peaks position iscalibrated by means of silicon internal standard.

The above anhydrous form of dasatinib designated Form B can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 7.2, 11.9, 14.4, 16.5, and 25.3±0.2degrees 2-theta; a powder XRD pattern with peaks at about 7.5, 14.4,16.5, 19.1 and 22.4±0.2 degrees 2-theta; a powder XRD pattern with peaksat about 7.2, 14.4, 16.5, 19.1 and 25.3±0.2 degrees 2-theta, a contentof water of about 0.5% by weight as measured by KF; and a content ofresidual solvents of about 0.5% by weight as measured by GC.

In addition, crystalline Dasatinib Form B has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms N-6 and H1-7 ormixtures thereof.

Typically, the amount of form N-6 in form B is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 12.4,13.2, 13.8 and 24.4 deg±0.2 degrees 2-theta, the amount of form H1-7 inform B is measured by PXRD using any peaks selected from the groupconsisting of peaks at: 4.6, 9.2, 15.2 and 19.6 deg±0.2 degrees 2-theta.

In addition anhydrous form B is relatively stable at a temperature ofabout 20° C. and below. As exemplified in example 91 and 92, form N6 isconverted to form B when slurried at a temperature of about 20° C. toabout 0° C. for 2 days.

Form B can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound 1, N-(2-hydroxyethyl) piperazine,N-ethyldiisopropylamine and a mixture of DMSO, methanol and water.

Typically, the crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO toobtain a solution comprising dasatinib, adding methanol and then waterto said solution to obtain a second solution, and precipitating saidcrystalline form to obtain a suspension.

Preferably, the reaction of compound 1, N-(2-hydroxyethyl)piperazine,and N-ethyldiisopropylamine in DMSO is done at a temperature of about40° C. to about 150° C., more preferably, of about 40° C. to about 100°C., most preferably, of about 60° C. to about 65° C. Preferably, thereaction is done upon stirring. Preferably, stirring is done for about 2hours.

Preferably, methanol and water are added at a temperature of about 60°C. to about 65° C.

Preferably, precipitation is done by cooling the solution. Preferably,cooling is to a temperature of about 5° C. to about 0° C.

The process for preparing form B of dasatinib can further compriserecovering the crystalline form. The recovery can be done for example,by filtering the suspension and drying.

Form B can also be prepared by another process comprising crystallizingdasatinib from a mixture comprising ethanol and water.

Typically, the crystallization comprises providing a solution ofdasatinib in a mixture of ethanol and water, and precipitating saidcrystalline form to obtain a suspension.

Preferably, the solution is provided by combining dasatinib and amixture of ethanol and water, and heating the combination. Preferably,heating is to a temperature of about 75° C. to about 80° C. Preferably,an additional amount of water is added prior to precipitating thecrystalline form, providing a solution. Preferably, the additionalamount of water is added at a temperature of about 75° C. to about 80°C. to obtain a solution.

Preferably, the solution can be maintained prior to precipitating thecrystalline form. Preferably, the solution is maintained at atemperature of about 70° C. Preferably, the solution is maintained forabout 1 hour.

Preferably, precipitation is done by cooling the second solution to atemperature of about 5° C. to about 0° C. Preferably, cooling can bedone over a period of about 1.5 hours to about 4 hours, more preferably,for a period of about 2 hours.

Typically, the suspension can be further maintained to increase theyield of the precipitated crystalline form. Preferably, the suspensioncan be further maintained at a temperature of about 5° C. to about 0° C.

Form B can also be prepared by another process comprising providing anopalescent solution of dasatinib in methanol, and precipitating saidcrystalline form to obtain a suspension.

Preferably, the opalescent solution is provided by combining dasatiniband methanol, and heating the combination. Preferably, heating is to atemperature of about 65° C.

Preferably, the opalescent solution is maintained at a temperature ofabout 65° C. Preferably, the solution is maintained for about 1 hour.

Preferably, precipitation is done by cooling the opalescent solution toa temperature of about 5° C. to about 0° C. Preferably, cooling can bedone over a period of about 1.5 hours to about 4 hours, more preferably,for a period of about 1 hour.

The process for preparing form B of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment, the present invention encompasses an-propanol-DMSO solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 6.0, 11.9, 12.0, 14.9, 17.8, 18.3, 18.7, 21.4,22.9, 24.2 and 24.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 1, and a combination thereof. This form can bedesignated as form K2.

In a preferred embodiment, the present invention encompasses an-propanol-DMSO solvate of dasatinib designated Form K2, characterizedby a PXRD pattern having any 5 peaks selected from the list consistingof: 6.0, 11.9, 12.0, 14.9, 17.8, 18.3, 18.7, 21.4, 22.9, 24.2 and24.7±0.2 degrees 2-theta.

The above n-propanol-DMSO solvate of dasatinib designated Form K2, canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 6.0, 12.0, 14.9, 17.8, and18.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.9,12.0, 21.4, 22.9 and 24.7±0.2 degrees 2-theta, a content of n-propanolof typically 9% by weight as measured by GC, and a content of DMSO oftypically 5% by weight as measured by GC.

In addition, crystalline Dasatinib Form K2 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form K2 is measured by PXRD usingany peaks selected from the group consisting of: 6.9, 12.4, 13.8 and16.8 deg±0.2 degrees 2-theta.

Form K2 can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound 1 of the following structure

N-(2-hydroxyethyl) piperazine, N-ethyldiisopropylamine and a mixture ofDMSO and n-propylalcohol.

Typically, the crystallization comprises reacting the compound offormula 1, N-(2-hydroxyethyl)piperazine, and N-thyldiisopropylamine inDMSO to obtain a solution comprising dasatinib and adding n-propylalcohol to said solution to obtain a suspension comprising saidcrystalline form.

Preferably, the reaction of a mixture of the compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 40° C. to about 150° C., more preferably,of about 40° C. to about 100° C., most preferably, of about 60° C. toabout 80° C.

Preferably, the reaction time is about 1 to about 2 hours. Preferably,when the reaction is done at about 60° C. the reaction time takes about2 h, and when done at about 80° C. the reaction time takes about 1 h.

Preferably, the reaction is done upon stirring. Preferably, stirring isdone for about 1 hour to about 3 hours depending on the reactiontemperature, more preferably, for about 2.75 hours.

Preferably, n-propanol is added at a temperature of about 80° C.

Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, cooling is to about roomtemperature.

Preferably, cooling can be conducted slowly, more preferably, over aperiod of about 90 minutes.

The process for preparing form K2 of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a DMSO solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 6.1, 11.8, 15.1, 16.6, 18.2, 19.3, 20.8, 21.6, 23.0, 23.8, 24.3,24.8 and 25.5±0.2 degrees 2-theta, a powder XRD pattern as depicted inFIG. 3; a solid-state ¹³C NMR spectrum having signals at about 139.1 and128.1±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shiftsdifferences between the signal exhibiting the lowest chemical shift at125±1.0 ppm and another in the chemical shift range of 100 to 180 ppm ofabout 13.9 and 2.9±0.1 ppm; and combination thereof. The signalexhibiting the lowest chemical shift in the chemical shift range of 100to 180 ppm is typically at about 125±1 ppm. This form can be designatedas form C.

In a preferred embodiment the present invention encompasses a DMSOsolvate of dasatinib designated form C, characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 6.1, 11.8,15.1, 16.6, 18.2, 19.3, 20.8, 21.6, 23.0, 23.8, 24.3, 24.8 and 25.5±0.2degrees 2-theta.

The above DMSO solvate of dasatinib can also be characterized by a PXRDpattern having peaks at about 6.1 and 20.8±0.2 degrees 2-theta and any 3peaks at positions selected from the group consisting of: 11.8, 15.1,18.2, 19.3 and 23.8±0.2 degrees 2-theta. The peak positions arecalibrated by means of silicon internal standard.

The above DMSO solvate of dasatinib designated Form C can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 6.1, 11.8, 15.1, 18.2, and 24.3±0.2degrees 2-theta; a powder XRD pattern with peaks at about 6.1, 15.1,18.2, 24.3 and 25.5±0.2 degrees 2-theta; a powder XRD pattern with peaksat about 11.8, 15.1, 18.2, 19.3 and 24.3±0.2 degrees 2-theta; and acontent of DMSO of about 11% to about 13% by weight, preferably about12% by weight as measured by GC; and a content of water of about 1% byweight as measured by KF.

In addition, crystalline Dasatinib Form C has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline dasatinib forms N-6 and H1-7.

Typically, the amount of form N-6 in form C is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.3 and21.2 deg±0.2 degrees 2-theta, the amount of form H1-7 in form C ismeasured by PXRD using any peaks selected from the group consisting ofpeaks at: 4.6, 9.2, 11.2, 13.8 and 19.6 deg±0.2 degrees 2-theta.

Form C can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound of formula 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and a mixture of DMSO and water.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO toobtain a solution comprising dasatinib, adding water, and precipitatingsaid crystalline form to obtain a suspension.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 40° C. to about 150° C., more preferably,of about 40° C. to about 100° C., most preferably, of about 40° C. toabout 60° C. Preferably, the reaction is done upon stirring. Preferably,stirring is done for about 1 hour to about 4 hours, preferably, forabout 2 hours to about 3 hours.

Preferably, water is added at a temperature of about 40° C. to about 60°C., providing a second solution.

Preferably, precipitation is done by cooling the second solution.Preferably, cooling is to a temperature of about 5° C. to about 0° C.

Optionally, the second solution can be further maintained prior toprecipitating the crystalline form. Preferably, the second solution isfurther maintained at a temperature of about 40° C. to about 60° C.,preferably of about 50° C. to about 60° C. Preferably, the secondsolution is further maintained for about 30 minutes.

The process for preparing form C of dasatinib can further compriserecovering the said crystalline form. The recovery can be done forexample, by filtering the suspension and drying.

In another embodiment the present invention encompasses a THF solvate ofdasatinib characterized by data selected from the group consisting of: aPXRD pattern having any 3 peaks selected from the list consisting of:5.9, 11.8, 12.2, 14.8, 18.3, 18.6, 21.5, 21.8, 24.5, 25.0, and 26.1±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 4, and acombination thereof. This form can be designated as form D.

In a preferred embodiment the present invention encompasses THF solvateof dasatinib designated form D, characterized by a PXRD pattern havingany 5 peaks selected from the list consisting of: 5.9, 11.8, 12.2, 14.8,18.3, 18.6, 21.5, 21.8, 24.5, 25.0, and 26.1±0.2 degrees 2-theta.

The above THF of dasatinib designated Form D can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.9, 12.2, 14.8, 25.0, and 26.1±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.9, 18.3,21.8, 24.5 and 26.1±0.2 degrees 2-theta, and a content of THF of about7% to about 9% by weight, preferably about 8% by weight as measured byGC.

In addition, crystalline Dasatinib Form D has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form D is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8, 16.8 and 21.1 deg±0.2 degrees 2-theta.

Form D can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound of formula 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and THF.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in THF toobtain a solution comprising dasatinib, and precipitating saidcrystalline form to obtain a suspension

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in THF is doneat reflux temperature. Preferably, reaction is done for about 8 hours.

Preferably, precipitation is done by cooling the solution. Preferably,cooling is to a temperature of about 5° C. to about 0° C.

The process for preparing form D of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a 2-methyl-THFsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 11.7, 12.8, 13.2, 17.5, 18.0, 18.4, 20.2, 22.8, 26.3and 27.0±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.5, and combination thereof. This form can be designated as form E.

In a preferred embodiment the present invention encompasses a2-methyl-THF solvate of dasatinib designated form E characterized by aPXRD pattern having any 5 peaks selected from the list consisting of:6.0, 11.7, 12.8, 13.2, 17.5, 18.0, 18.4, 20.2, 22.8, 26.3 and 27.0±0.2degrees 2-theta.

The above 2-methyl-THF solvate of dasatinib designated Form E can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 11.7, 17.5, 20.2, and26.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 6.0,11.7, 18.0, 20.2 and 22.8±0.2 degrees 2-theta, and a content of2-methyl-THF of about 3% to about 5%, preferably about 4% by weight asmeasured by GC.

In addition, crystalline Dasatinib Form E has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form E is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 12.4,16.8, 21.1, 24.4 and 24.9 deg±0.2 degrees 2-theta.

Form E can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound of formula 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and 2-methyl-THF.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in2-methyl-THF to obtain a solution comprising dasatinib, andprecipitating said crystalline form to obtain a suspension

Preferably, the reaction of compound 1, N-(2-hydroxyethyl)piperazine,and N-ethyldiisopropylamine in 2-methyl-THF is done at refluxtemperature. Preferably, the reaction is done for about 2 hours to about4 hours, more preferably for about 3 hours.

Preferably, precipitation is done by cooling the solution. Preferably,cooling is to a temperature of about 5° C. to about 0° C.

The process for preparing form E of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a 1,4-dioxanesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 12.0, 14.9, 17.9, 18.2, 18.8, 20.8, 21.2, 22.8, 24.124.1, 24.6 and 25.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 6, and a combination thereof. This form can bedesignated as form F.

In a preferred embodiment the present invention encompasses a1,4-dioxane solvate of dasatinib designated form F characterized by aPXRD pattern having any 5 peaks selected from the list consisting of:6.0, 12.0, 14.9, 17.9, 18.2, 18.8, 20.8, 21.2, 22.8, 24.1 24.1, 24.6 and25.7±0.2 degrees 2-theta.

The above 1,4-dioxane solvate of dasatinib designated Form F can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 12.0, 14.9, 24.1, and24.6±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 6.0,14.9, 17.9, 18.8 and 21.2±0.2 degrees 2-theta, and a content of1,4-dioxane of about 10% to about 12%, preferably about 11% by weight asmeasured by GC.

In addition, crystalline Dasatinib Form F has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form F is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 12.4,13.2, 13.8 and 16.8 deg±0.2 degrees 2-theta.

Form F can be prepared by a process comprising precipitating dasatinibfrom a mixture comprising the compound of formula 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and 1,4-dioxane.

The precipitation comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in 1,4-dioxaneto obtain a suspension comprising said crystalline dasatinib.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in 1,4-dioxaneis done at reflux temperature. Preferably, the reaction is done forabout 2 hours to about 4 hours, more preferably for about 3 hours.

Typically, the suspension can be cooled to increase the yield of theprecipitated crystalline form. Preferably, the suspension is cooled at atemperature of about 5° C. to about 0° C.

The process for preparing form F of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a pyridinesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.7, 12.3, 14.0, 18.3, 21.4, 22.0, 22.7, 24.7, and25.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 7,and combination thereof. This form can be designated as form G.

In a preferred embodiment the present invention encompasses a pyridinesolvate of dasatinib designated form G characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 5.9, 11.7,12.3, 14.0, 18.3, 21.4, 22.0, 22.7, 24.7, and 25.2±0.2 degrees 2-theta.

The above pyridine solvate of dasatinib designated Form G can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.9, 12.3, 14.0, 24.7, and 25.2±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.9, 12.3,14.0, 22.4 and 25.2±0.2 degrees 2-theta, and a content of pyridine ofabout 4% to about 6% by weight, preferably about 5% by weight asmeasured by GC.

In addition, crystalline Dasatinib Form G has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form G is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2 and16.8 deg±0.2 degrees 2-theta.

Form G can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound of formula 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and a solvent selected from thegroup consisting of: a mixture of pyridine and acetone and a mixture ofpyridine and ethylacetate.

The crystallization comprises reacting compound of formula 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in pyridine toobtain a solution comprising dasatinib, and adding acetone orethylacetate to obtain a suspension comprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in pyridine isdone at a temperature of about 80° C. to about 100° C., more preferably,of about 90° C. to about 100° C. Preferably, the reaction is done uponstirring. Preferably, stirring is done for about 2.5 to about 5 hours,more preferably, for about 2.5 to about 3 hours.

Preferably, acetone or ethylacetate are added at a temperature of about90° C. to about 100° C., providing the suspension.

Typically, the suspension can be cooled to increase the yield of theprecipitated crystalline form. Preferably, suspension is cooled to aroom temperature.

The process for preparing form G of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a toluenesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 12.0, 15.0, 15.4, 16.9, 19.3, 21.3, 21.7, 23.4, 24.1and 24.8±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.8, and a combination thereof. This form can be designated as form H.

In a preferred embodiment the present invention encompasses a toluenesolvate of dasatinib designated form H characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 6.0, 12.0,15.0, 15.4, 16.9, 19.3, 21.3, 21.7, 23.4, 24.1 and 24.8±0.2 degrees2-theta.

The above toluene of dasatinib designated Form H can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 6.0, 12.0, 15.4, 21.7, and 24.8±0.2degrees 2-theta; a powder XRD pattern with peaks at about 6.0, 12.0,15.4, 24.1 and 24.8±0.2 degrees 2-theta, and a content of toluene ofabout 5% to about 7% by weight, preferably about 6% by weight asmeasured by GC.

In addition, crystalline Dasatinib Form H has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form H is measured by PXRD usingany peaks from selected the group consisting of peaks at: 6.9 and 13.8deg±0.2 degrees 2-theta.

Form H can be prepared by a process comprising precipitating dasatinibfrom a mixture comprising the compound 1, N-(2-hydroxyethyl) piperazine,N-ethyldiisopropylamine and toluene.

The precipitation comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in toluene toobtain a suspension comprising said crystalline dasatinib.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in toluene isdone at reflux temperature, preferably, reflux temperature is at about110° C. to about 111° C. Preferably, reaction is done for about 8 hoursto about 12 hours, more preferably about 9 hours.

Typically, the suspension can be cooled to increase the yield of theprecipitated crystalline form. Preferably, the suspension is cooled at atemperature of about 5° C. to about 0° C.

The process for preparing form H of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a MIBK solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 5.8, 10.2, 11.4, 12.5, 17.3, 17.8, 20.0, 21.9, 22.6, 25.8 and26.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 9,and combination thereof. This form can be designated as form I.

In a preferred embodiment the present invention encompasses a MIBKsolvate of dasatinib designated Form I characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 5.8, 10.2,11.4, 12.5, 17.3, 17.8, 20.0, 21.9, 22.6, 25.8 and 26.2±0.2 degrees2-theta.

The above MIBK solvate of dasatinib designated Form I can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.8, 10.2, 17.3, 20.0, and 25.8±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.8, 10.2,20.0, 22.6 and 25.8±0.2 degrees 2-theta, and a content of MIBK of about8% to about 10% by weight, preferably about 9% by weight as measured byGC.

In addition, crystalline Dasatinib Form I has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form I is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8, 16.8, 21.1 and 24.4 deg±0.2 degrees 2-theta.

Form I can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound of formula 1, N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine and a mixture of pyridine and MIBK.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in pyridine toobtain a solution comprising dasatinib, and adding MIBK to obtain asuspension comprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in pyridine isdone at a temperature of about 80° C. to about 100° C., more preferably,at about 100° C. Preferably, the reaction is done upon stirring.Preferably, stirring is done for about 2.5 hours to about 5 hoursdepending on the reaction temperature, more preferably, for about 2.5hours.

Preferably, MIBK is added at a temperature of about 100° C., providingthe suspension.

Typically, the suspension can be cooled to increase the yield of theprecipitated crystalline form. Preferably, the suspension is cooled to atemperature of about room temperature to about 0° C., more preferably,to about room temperature.

The process for preparing form I of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

In another embodiment the present invention encompasses a mono acetonesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.7, 12.3, 14.7, 17.6, 18.5, 21.4, 22.1, 22.8, 24.7and 25.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.10, and combination thereof. This form can be designated as form J.

In a preferred embodiment the present invention encompasses a monoacetone solvate of dasatinib designated Form J characterized by a PXRDpattern having any 5 peaks selected from the list consisting of: 5.9,11.7, 12.3, 14.7, 17.6, 18.5, 21.4, 22.1, 22.8, 24.7 and 25.2±0.2degrees 2-theta.

The above mono acetone solvate of dasatinib designated Form J can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 11.7, 12.3, 14.7, and17.6±0.2 degrees 2-theta, and a content of acetone of about 8% to about10% by weight, preferably about 9% by weight as measured by GC; and awater content of up to 0.5% by weight as measured by Karl-Fischer.

In addition, crystalline Dasatinib Form J has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form J is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8, 16.8, and 24.4 deg±0.2 degrees 2-theta.

Form J can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound 1, N-(2-hydroxyethyl) piperazine,N-ethyldiisopropylamine and a solvent selected from the group consistingof: mixture of DMSO and acetone, and a mixture of DMF and acetone.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO or inDMF to obtain a solution comprising dasatinib, and adding acetone toobtain a suspension comprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO or inDMF is done at a temperature of about 40° C. to about 150° C.Preferably, the reaction with DMSO is done at a temperature of about 40°C. to about 150° C., preferably, at about 40° C. to about 100° C., morepreferably, at about 60° C. to about 80° C. Preferably, the reactionwith DMF is done at a temperature of about 90° C. to about 100° C.Preferably, the reaction is done upon stirring. Preferably, stirring isdone for about 1 hour to about 3 hours. Preferably, the reaction inDMSO, is stirred for about 1 hour to about 2 hours. Preferably, thereaction with DMF, is stirred for about 2.5 hour to about 3 hours.

Preferably, acetone is added at a temperature of about 60° C. to about100° C., providing the suspension.

Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, cooling is to about roomtemperature.

Optionally, when the solvent mixture is DMSO and acetone, water can beadded to the suspension providing a second solution. Preferably, wateris added at a temperature of about 60° C. to about 80° C. Preferably,the second solution is cooled to obtain said suspension. Preferably,cooling is to a temperature of about 5° C. to about 0° C.

The process for preparing form J of dasatinib can further compriserecovering the said crystalline form. The recovery can be done forexample, by filtering the suspension and drying.

In another embodiment the present invention encompasses a 2-butanol-DMSOsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 12.0, 14.9, 17.9, 18.2, 18.9, 21.1, 22.8, 24.0,24.5, 25.6 and 26.1±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 12, and a combination thereof. This form can bedesignated as form L2.

In a preferred embodiment the present invention encompasses a2-butanol-DMSO solvate of dasatinib designated Form L2 characterized bya PXRD pattern having any 5 peaks selected from the list consisting of:6.0, 12.0, 14.9, 17.9, 18.2, 18.9, 21.1, 22.8, 24.0, 24.5, 25.6 and26.1±0.2 degrees 2-theta.

The above 2-butanol-DMSO solvate of dasatinib designated Form L2 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 12.0, 14.9, 21.1 and24.5±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 14.9,17.9, 21.1, 24.0 and 24.9±0.2 degrees 2-theta, a content of 2-butanol oftypically 9% to about 11%, preferably about 10% by weight as measured byGC, and a content of DMSO of about 4% to about 6%, preferably about 5%by weight as measured by GC.

In addition, crystalline Dasatinib Form L2 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form L2 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8 and 16.8 deg±0.2 degrees 2-theta.

Form L2 can be prepared by a process comprising crystallizing dasatinibfrom a mixture comprising the compound 1, N-(2-hydroxyethyl) piperazine,N-ethyldiisopropylamine and a mixture of DMSO and 2-butanol.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO toobtain a solution comprising dasatinib, adding 2-butanol, andprecipitating said crystalline form to obtain a suspension comprisingsaid crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 40° C. to about 150° C., more preferably,at about 40° C. to about 100° C., more preferably, at about 60° C. toabout 80° C., most preferably, at about 80° C. to about 85° C.Preferably, the reaction is done for about 1 hour to about 2 hoursdepending on the reaction temperature.

Preferably, 2-butanol is added at a temperature of about 80° C. to about85° C., providing a second solution.

Preferably, precipitation is induced by cooling the second solution.Preferably, cooling is to a temperature of about 5° C. to about 0° C.

The process for preparing form L2 of dasatinib can further compriserecovering said crystalline form. The recovery can be done for example,by filtering the suspension and drying.

Also described by the present invention is a mixture of a hydrate formof dasatinib, designated form M characterized by a PXRD pattern havingany 5 peaks selected from the list consisting of: 5.5, 10.8, 16.0, 22.3,25.4, and 27.1±0.2 degrees 2-theta; and a pyridine solvate, designatedform G characterized by a PXRD pattern having any 5 peaks selected fromthe list consisting of: 5.9, 11.7, 12.3, 14.0, 18.3, 21.4, 22.0, 22.7,24.7, and 25.2±0.2 degrees 2-theta.

This mixture of hydrate form of dasatinib, designated form M, and apyridine solvate, designated form G is characterized by a powder XRDpattern as depicted in FIG. 13.

Form M can be further characterized by a powder XRD pattern with peaksat about 5.5, 16.0, 22.3, 25.4 and 27.1±0.2 degrees 2-theta

The mixture of hydrate form of dasatinib, designated form M, and apyridine solvate, designated form G can be further characterized by awater content of about 3% by weight as measured by KF and a pyridinecontent of about 6% to about 8% by weight, preferably about 7% by weightas measured by GC.

In addition, crystalline Dasatinib Form M has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7.

Typically, the amount of form N-6 in form M is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8 and 16.8 deg±0.2 degrees 2-theta and the amount of form H1-7 inform M is measured by PXRD using any peaks selected from the groupconsisting of peaks at: 4.6, 11.2, 15.2, 18.0 and 19.5 deg±0.2 degrees2-theta.

The mixture of Forms G and M can be prepared by a process comprisingcrystallizing dasatinib from a mixture comprising the compound 1,N-(2-hydroxyethyl) piperazine, N-ethyldiisopropylamine and a mixture ofpyridine and water.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in pyridine toobtain a solution comprising dasatinib, and adding water to obtain asuspension comprising said mixture of crystalline forms.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in pyridine isdone at a temperature of about 80° C. to about 100° C., preferably, at atemperature of about 80° C. Preferably, the reaction is done for about2.5 hours to about 5 hours, more preferably for about 3 hours to about 4hours, depending on the reaction temperature.

Preferably, water is added at a temperature of about 80° C., providingthe suspension.

Typically, the suspension is cooled to increase the yield of theprecipitated mixture of crystalline forms. Preferably, cooling is toabout room temperature.

The process for preparing the mixture of crystalline forms G and M ofdasatinib can further comprise recovering said mixture of crystallineforms. The recovery can be done for example, by filtering the suspensionand drying.

The present invention encompasses amorphous dasatinib.

The present invention encompasses an amorphous dasatinib characterizedby data selected from the group consisting of: a powder XRD pattern asdepicted in FIG. 16, a powder XRD pattern as depicted in FIG. 99, apowder XRD pattern as depicted in FIG. 35, a powder XRD pattern asdepicted in FIG. 43, and a combination thereof.

In addition, crystalline Dasatinib amorphous has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7.

Typically, the amount of form N-6 in amorphous is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 12.4,13.2, 13.8, 16.8, 21.1, 24.4 and 24.9 deg±0.2 degrees 2-theta and theamount of form H1-7 in amorphous is measured by PXRD using any peaksselected from the group consisting of peaks at: 4.6, 9.2, 11.2, 15.2,18.0 and 19.5 deg±0.2 degrees 2-theta.

The amorphous form of dasatinib can be prepared by a process comprisingreacting compound 1, N-(2-hydroxyethyl)piperazine, andN-ethyldiisopropylamine in DMF to obtain a solution comprisingdasatinib, cooling the solution, and adding water to obtain a suspensioncomprising said amorphous form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF is doneat a temperature of about 90° C. to about 100° C., preferably, at atemperature of about 90° C. Preferably, the reaction is done for about2.5 hours to about 3 hours, more preferably, for about 2.5 hours.

Preferably, the cooling is to a temperature of about 0° C.

Preferably, water is added at a temperature of about 0° C., providingthe suspension.

The process for preparing the amorphous form of dasatinib can furthercomprise recovering said form. The recovery can be done for example, byfiltering the suspension and drying.

Amorphous dasatinib can also be prepared by a process comprisingsuspending dasatinib form A21 in a solvent selected from the groupconsisting of 1,2-dichlorobenzene, propylene glycol, or mixturesthereof.

Preferably, the suspension is heated to a temperature of about 50° C.Preferably, the suspension is maintained at this temperature for about 6hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 25° C.

The amorphous form can then be recovered from the suspension byevaporating the solvent. Preferably, the solvent is removed at aboutroom temperature. Preferably, the solvent is removed at atmosphericpressure.

Preferably, the amorphous form is maintained at atmospheric pressure,preferably, at about room temperature, preferably, for a period ofovernight.

The amorphous as depicted in FIG. 35 can be prepared by a processcomprising suspending form A21 of dasatinib in ethyleneglycol.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably to about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

The amorphous can then be recovered from the suspension by evaporatingthe solvent. Preferably, the solvent is removed at about roomtemperature. Preferably, the solvent is removed at atmospheric pressure.

Preferably, the amorphous is maintained at atmospheric pressure,preferably, at about room temperature, preferably, for a period ofovernight.

The amorphous as depicted in FIG. 43 can be prepared by a processcomprising suspending form A21 of dasatinib in glycerol.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably of about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

The amorphous can then be recovered from the suspension by evaporatingthe solvent. Preferably, the solvent is removed at about roomtemperature. Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining Theamorphous at atmospheric pressure, preferably, at about roomtemperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses an IPA-DMFsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.0, 14.9, 17.8, 18.2, 18.7, 21.4, 22.8, 24.2and 24.7±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.17, and a combination thereof. This form can be designated as form A1.

In a preferred embodiment, the present invention encompasses an IPA-DMFsolvate of dasatinib designated Form A1, characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 5.9, 11.8,12.0, 14.9, 17.8, 18.2, 18.7, 21.4, 22.8, 24.2 and 24.7±0.2 degrees2-theta.

The above IPA-DMF solvate of dasatinib designated Form A1 can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.9, 11.8, 14.9, 17.8, and 18.2±0.2degrees 2-theta; a powder XRD pattern with peaks at about 11.8, 11.8,21.4, 22.8 and 24.7±0.2 degrees 2-theta, a content of IPA of about 8% toabout 10% by weight, preferably about 9% by weight as measured by GC,and a content of DMF of about 2% to about 4% by weight, preferably about3% by weight as measured by GC.

In addition, crystalline Dasatinib Form A1 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form A1 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.2,13.8 and 16.8 deg±0.2 degrees 2-theta.

Form A1 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture comprising the compound 1,N-(2-hydroxyethyl) piperazine, N-ethyldiisopropylamine and a mixture ofDMF and IPA.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF toobtain a solution comprising dasatinib, and adding IPA to obtain asuspension comprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF is doneat a temperature of about 90° C. to about 100° C., preferably, at atemperature of about 90° C. Preferably, the reaction is done for about2.5 hours to about 4 hours, more preferably, for about 2.5 hours.

Preferably, IPA is added at a temperature of about 100° C., providingthe suspension.

Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, cooling is to about roomtemperature to about 0° C., more preferably, to about 20° C. to about 0°C.

The process for preparing form A1 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

In another embodiment, the present invention encompasses an-propanol-DMF solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.9, 11.8, 12.2, 14.9, 17.7, 18.3, 18.6, 21.4,21.7, 24.4 and 24.9±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 19, and combination thereof. This form can bedesignated as form K1.

In a preferred embodiment, the present invention encompasses an-propanol-DMF solvate of dasatinib designated Form K1, characterized bya PXRD pattern having any 5 peaks selected from the list consisting of:5.9, 11.8, 12.2, 14.9, 17.7, 18.3, 18.6, 21.4, 21.7, 24.4 and 24.9±0.2degrees 2-theta.

The above n-propanol-DMF solvate of dasatinib designated Form K1 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 11.8, 12.2, 14.9, 17.7 and18.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.8,12.2, 21.4, 22.7 and 24.9±0.2 degrees 2-theta, a content of n-propanolof about 8% to about 10%, preferably about 9% by weight as measured byGC, and a content of DMF of about 2% to about 4%, preferably about 3% byweight as measured by GC.

In addition, crystalline Dasatinib Form K1 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form K1 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.8 and21.1 deg±0.2 degrees 2-theta.

Form K1 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture comprising the compound 1,N-(2-hydroxyethyl) piperazine, N-ethyldiisopropylamine and a mixture ofDMF and n-propanol.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF toobtain a solution comprising dasatinib, and adding n-propanol to obtaina suspension comprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF is doneat a temperature of about 90° C. to about 100° C., more preferably, atabout 100° C. Preferably, the reaction is done for about 2.5 hours toabout 4 hours, more preferably, for about 2.5 hours.

Preferably, n-propanol is added at a temperature of about 100° C.,providing the suspension.

Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, cooling is to a temperatureof about 20° C. to about 0° C., more preferably, to about roomtemperature.

The process for preparing form K1 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

In another embodiment, the present invention encompasses a n-propanolsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.1, 14.9, 17.8, 18.3, 18.7, 21.5, 21.6,22.8, 24.3 and 24.8±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 20, and a combination thereof. This form can bedesignated as form K3.

In a preferred embodiment, the present invention encompasses an-propanol solvate of dasatinib designated Form K3, characterized by aPXRD pattern having any 5 peaks selected from the list consisting of:5.9, 11.8, 12.1, 14.9, 17.8, 18.3, 18.7, 21.5, 21.6, 22.8, 24.3 and24.8±0.2 degrees 2-theta.

The above n-propanol solvate of dasatinib designated Form K3 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 11.8, 12.1, 14.9, 17.8 and18.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.8,12.1, 21.5, 22.8 and 24.8±0.2 degrees 2-theta, and a content ofn-propanol of about 10% to about 12% by weight, preferably about 11% byweight as measured by GC.

In addition, crystalline Dasatinib Form K3 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7.

Typically, the amount of form N-6 in form K3 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 12.4,13.8, 16.8 and 21.1 deg±0.2 degrees 2-theta and the amount of form H1-7in form K3 is measured by PXRD using any peaks selected from the groupconsisting of peaks at: 4.6, 9.2, 11.2, 15.2 and 19.5 deg±0.2 degrees2-theta.

Form K3 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture of n-propanol and water.

The crystallization comprises providing a solution of dasatinib in amixture of n-propanol and water, and precipitating said crystalline formto obtain a suspension.

Preferably, the solution is provided by combining dasatinib, n-propanoland water, and heating the combination. Preferably, heating is to aboutreflux temperature.

Preferably, precipitation is obtained by cooling the solution.Preferably, cooling is to a temperature of about 20° C. to about 0° C.,more preferably, to a temperature of about 5° C. to about 0° C.

The process for preparing form K3 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

Form K3 of dasatinib can also be prepared by a process comprisingsuspending form A21 of dasatinib in n-propanol.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 to about 8 hours, preferablyabout 6 hours.

Preferably, the heated suspension is then cooled and maintained forabout 10 hours to about 14 hours, preferably overnight. Preferably, theheated suspension is cooled and maintained at a temperature of about 20°C. to about 30° C., preferably about 25° C.

Form K3 can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

In another embodiment, the present invention encompasses a 2-butanol-DMFsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.7, 12.0, 14.7, 17.6, 18.1, 18.6, 21.4, 22.6,24.1, 24.6 and 25.7±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 21, and a combination thereof. This form can bedesignated as form L1.

In a preferred embodiment, the present invention encompasses a2-butanol-DMF solvate of dasatinib designated Form L1, characterized bya PXRD pattern having any 5 peaks selected from the list consisting of:5.9, 11.7, 12.0, 14.7, 17.6, 18.1, 18.6, 21.4, 22.6, 24.1, 24.6 and25.7±0.2 degrees 2-theta.

The above 2-butanol-DMF solvate of dasatinib designated Form L1 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 12.0, 14.7 and 17.6±0.2degrees 2-theta; a powder XRD pattern with peaks at about 11.7, 12.0,21.4, 22.6 and 24.6±0.2 degrees 2-theta, a content of 2-butanol of about10% to about 12% by weight, preferably about 11% by weight as measuredby GC, and a content of DMF of about 2% to about 4% by weight,preferably about 3% by weight as measured by GC.

In addition, crystalline Dasatinib Form L1 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7.

Typically, the amount of form N-6 in form L1 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.3,13.8 and 16.8 deg ±0.2 degrees 2-theta.

Form L1 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture comprising the compound 1,N-(2-hydroxyethyl) piperazine, N-ethyldiisopropylamine and a mixture ofDMF and 2-butanol.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF toobtain a solution comprising dasatinib, and adding 2-butanol to obtain asuspension comprising said crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF is doneat a temperature of about 90° C. to about 100° C., more preferably, toabout 100° C. Preferably, the reaction is done for about 2.5 hours toabout 4 hours, more preferably, for about 4 hours.

Preferably, 2-butanol is added at a temperature of about 100° C.,providing the suspension.

Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, cooling is to a temperatureof about 20° C. to about 0° C., more preferably, of about 5° C. to about0° C.

The process for preparing form L1 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

In one embodiment, the present invention encompasses a 2-butanol solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 5.9, 11.8, 12.0, 14.7, 17.7, 18.1, 18.7, 21.3, 22.6, 24.1 and24.6±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 22,and a combination thereof. This form can be designated as form L3.

In a preferred embodiment, the present invention encompasses a 2-butanolsolvate of dasatinib designated Form L3, characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 5.9, 11.8,12.0, 14.7, 17.7, 18.1, 18.7, 21.3, 22.6, 24.1 and 24.6±0.2 degrees2-theta.

The above 2-butanol solvate of dasatinib designated Form L3 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 12.0, 14.7, 17.7 and18.7±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.8,12.0, 21.3, 22.6 and 24.6±0.2 degrees 2-theta, and a content of2-butanol of about 12% to about 14% by weight, preferably about 13% byweight as measured by GC.

In addition, crystalline Dasatinib Form L3 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms: N-6 and H1-7.

Typically, the amount of form N-6 in form L3 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.3,13.8, and 16.8 deg ±0.2 degrees 2-theta and the amount of form H1-7 inform L3 is measured by PXRD using any peaks selected from the groupconsisting of peaks at: 4.6, 11.2, 15.2 and 19.5 deg±0.2 degrees2-theta.

Form L3 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture of 2-butanol and water.

The crystallization comprises providing a solution of dasatinib in amixture of 2-butanol and water, and precipitating said crystalline formto obtain a suspension.

Preferably, the solution is provided by combining dasatinib and2-butanol, heating the combination and adding water. Preferably, thecombination of dasatinib and 2-butanol provides a suspension.Preferably, the suspension is heated to a temperature of about reflux.To the heated suspension is then added water, providing the solution.

Preferably, the solution is further maintained prior to precipitation ofthe said crystalline form. Preferably, the solution is furthermaintained at about reflux temperature. Preferably, the solution isfurther maintained for about 20 minutes to about 60 minutes, morepreferably, for about an hour.

Preferably, precipitation is obtained by cooling the solution.Preferably, cooling is to a temperature of about 20° C. to about 0° C.,more preferably, of about 5° C. to about 0° C.

The process for preparing form L3 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

In another embodiment, the present invention encompasses an-butanol-DMSO solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.9, 11.9, 12.0, 14.8, 17.8, 18.2, 18.7, 21.3,22.7, 24.1 and 24.6±0.2 degrees 2-theta, a powder XRD pattern asdepicted in FIG. 23, and a combination thereof. This form can bedesignated as form N2.

In a preferred embodiment, the present invention encompasses an-butanol-DMSO solvate of dasatinib designated Form N2, characterized bya PXRD pattern having any 5 peaks selected from the list consisting of:5.9, 11.9, 12.0, 14.8, 17.8, 18.2, 18.7, 21.3, 22.7, 24.1 and 24.6±0.2degrees 2-theta.

The above n-butanol-DMSO solvate of dasatinib designated Form N2 can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 12.0, 14.8, 17.8 and18.7±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.9,12.0, 21.3, 22.7 and 24.6±0.2 degrees 2-theta, a content of n-butanol ofabout 10% as measured by GC, and a content of DMSO of about 5% [pleaseprovide range if possible] by weight as measured by GC.

In addition, crystalline Dasatinib Form N2 has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib form N-6.

Typically, the amount of form N-6 in form N2 is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 13.3,13.8, and 16.8 deg±0.2 degrees 2-theta.

Form N2 of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from a mixture comprising the compound 1,N-(2-hydroxyethyl) piperazine, N-ethyldiisopropylamine and a mixture ofDMSO and n-butanol.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO toobtain a solution comprising dasatinib, adding n-butanol, andprecipitating said crystalline form to obtain a suspension.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 40° C. to about 150° C., more preferably,at about 40° C. to about 100° C., more preferably, at about 60° C. toabout 80° C., most preferably, at about 80° C. to about 85° C.Preferably, the reaction is done for about 1 hour to about 2 hoursdepending on the reaction temperature.

Preferably, 2-butanol is added at a temperature of about 80° C. to about85° C., providing a second solution.

Preferably, precipitation is achieved by cooling the second solution.Preferably, cooling is to a temperature of about 20° C. to about 0° C.,more preferably, of about 5° C. to about 0° C.

The process for preparing form N2 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

In another embodiment, the present invention encompasses a DMF-watersolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.4, 10.8, 12.1, 14.8, 16.4, 21.4, 22.1, 24.2, 24.8 and25.4±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 24,and combination thereof. This form can be designated as form P.

In a preferred embodiment, the present invention encompasses a DMF-watersolvate of dasatinib designated Form P, characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 5.4, 10.8,12.1, 14.8, 16.4, 21.4, 22.1, 24.2, 24.8 and 25.4±0.2 degrees 2-theta.

The above DMF-water solvate of dasatinib designated Form P can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.4, 10.8, 12.1, 16.4 and25.4±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 5.4,12.1, 16.4, 24.2 and 25.4±0.2 degrees 2-theta, a content of water ofabout 6 to about 7% by weight as measured by KF, and a content of DMF ofabout 11% to about 13% by weight, preferably about 12% by weight asmeasured by TGA.

Form P can be prepared by a process comprising dissolving datatinib inDMF and admixing the solution with water to obtain a suspensioncomprising said crystalline form.

Preferably, the dissolution is done at about 100° C. Preferably, wateris added to the solution. Preferably, the addition of water is done atabout 100° C.

Typically, the suspension is cooled to increase the yield of theprecipitated crystalline form. Preferably, the cooling is to about roomtemperature.

The process to prepare crystalline form P can further compriserecovering said crystalline form from the suspension. The recovery canbe done for example by filtering the suspension and drying the filteredproduct.

In another embodiment, the present invention encompasses a DMF solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 5.8, 11.5, 12.3, 14.6, 17.3, 18.2, 21.2, 22.1, 22.6, 24.7 and25.2±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG. 25,and a combination thereof. This form can be designated as form Q.

In a preferred embodiment, the present invention encompasses a DMFsolvate of dasatinib designated Form Q, characterized by a PXRD patternhaving any 5 peaks selected from the list consisting of: 5.8, 11.5,12.3, 14.6, 17.3, 18.2, 21.2, 22.1, 22.6, 24.7 and 25.2±0.2 degrees2-theta.

The above DMF solvate of dasatinib designated Form Q can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.8, 12.3, 14.6, 18.2 and 25.2±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.8, 12.3,14.6, 17.3 and 22.6±0.2 degrees 2-theta, a content of water of about 1%by weight as measured by KF, and a content of DMF of about 11% to about13% by weight, preferably about 12% by weight as measured by TGA.

Form Q can be prepared by a process comprising heating dasatinib form Pto a temperature of about 70° C. at atmospheric pressure.

In another embodiment, the present invention encompasses a MIPK solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern any 3 peaks selected from the list consisting of:5.7, 12.0, 14.6, 18.0, 18.2, 22.4 and 24.6±0.2 degrees 2-theta, a powderXRD pattern as depicted in FIG. 26, and a combination thereof. This formcan be designated as form AA.

In a preferred embodiment, the present invention encompasses a MIPKsolvate of dasatinib designated form AA characterized by a PXRD patternhaving peaks at about 14.6 and 24.6±0.2 degrees 2-theta and any 3 peaksselected from the list consisting of: 5.7, 12.0, 18.0, 18.2 and 22.4±0.2degrees 2-theta.

The above MIPK solvate of dasatinib designated Form AA can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.7, 12.0, 14.6, 18.0 and 18.2±0.2degrees 2-theta; a powder XRD pattern with peaks at about 14.6, 18.0,18.2, 22.4 and 24.6±0.2 degrees 2-theta; and a weight loss on drying ofabout 15% by weight as measured by TGA.

Form AA can be prepared by a process comprising suspending form A21 ofdasatinib in methyl-isopropylketone at a temperature of about 50° C. fora period of about 6 hours, and cooling the suspension to a temperatureof about of 25° C. for a period of about overnight.

Form AA can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AA is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses adimethoxyethane solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.7, 6.0, 11.4, 16.8, 19.7 and 24.1±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 27, and a combinationthereof. This form can be designated as form AB.

In another embodiment, the present invention encompasses adimethoxyethane solvate of dasatinib designated form AB characterized byPXRD pattern having peaks at about 5.7 and 11.4±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 6.0, 16.8, 19.7 and24.1±0.2 degrees 2-theta.

The above dimethoxyethane solvate of dasatinib designated Form AB can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.7, 6.0, 11.4, 19.7 and 24.1±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.7, 11.4,16.8, 19.7 and 24.1±0.2 degrees 2-theta; and a weight loss on drying ofabout 14% to about 16%, preferably about 15% by weight as measured byTGA.

Form AB can be prepared by a process comprising suspending form A21 ofdasatinib in dimethoxyethane.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably to about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for an overnightperiod. Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

Form AB can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AB is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a cellosolvesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.5, 11.1, 11.6, 15.7, 16.8 and 23.4±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 28, and a combination thereof.This form can be designated as form AC.

In a preferred embodiment, the present invention encompasses acellosolve solvate of dasatinib designated Form AC characterized by aPXRD pattern having peaks at about 5.5 and 11.1±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 11.6, 15.7, 16.8 and23.4±0.2 degrees 2-theta.

In another embodiment, the present invention encompasses a cellosolvesolvate of dasatinib designated Form AC, characterized by a powder XRDpattern as depicted in FIG. 28.

The above cellosolve solvate of dasatinib designated Form AC can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.5, 11.6, 15.7 and 16.8±0.2degrees 2-theta; a powder XRD pattern with peaks at about 11.1, 11.6,16.8 and 23.4±0.2 degrees 2-theta; and a weight loss on drying of about40% to about 50% by weight, preferably about 45% by weight, as measuredby TGA.

Form AC can be prepared by a process comprising suspending form A21 ofdasatinib in cellosolve.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably to about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for an overnightperiod. Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably to about 25° C.

Form AC can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AC is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a methylacetatesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.1, 14.8, 17.7, 18.2 and 21.6±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 29, and a combinationthereof. This form can be designated as form AD.

In a preferred embodiment, the present invention encompasses amethylacetate solvate of dasatinib designated Form AD characterized by aPXRD pattern having peaks at about 12.1 and 21.6±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 5.9, 11.8, 14.8, 17.7and 18.2±0.2 degrees 2-theta.

The above methylacetate solvate of dasatinib designated Form AD can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 12.1, 14.8 and 17.7±0.2degrees 2-theta; a powder XRD pattern with peaks at about 12.1, 14.8,18.2 and 21.6±0.2 degrees 2-theta; and a weight loss on drying of about9% to about 11% by weight, preferably about 10% by weight, as measuredby TGA.

Form AD can be prepared by a process comprising suspending form A21 ofdasatinib in methylacetate.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably to about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for an overnightperiod. Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably at about 25° C.

Form AD can then be recovered from the suspension by evaporatingsolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AD is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a methanolsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 7.1, 11.9, 12.7, 14.3, 16.0, 19.1 and 21.6±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 30, and a combinationthereof. This form can be designated as form AE.

In a preferred embodiment, the present invention encompasses a methanolsolvate of dasatinib designated Form AE characterized by a PXRD patternhaving peaks at about 7.1 and 14.3±0.2 degrees 2-theta and any 3 peaksselected from the list consisting of: 11.9, 12.7, 16.0, 19.1 and21.6±0.2 degrees 2-theta.

The above methanol solvate of dasatinib designated Form AE can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 7.1, 11.9, 16.0, 19.1 and21.6±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.1,12.7, 14.3, 16.0 and 19.1±0.2 degrees 2-theta; and a weight loss ondrying of about 2% to about 4%, preferably about 3% by weight asmeasured by TGA

Form AE can be prepared by a process comprising providing a solution ofdasatinib in methanol, and precipitating said crystalline form bycooling to a temperature of about 5° C. to about 0° C. to obtain asuspension.

Form A21 is dissolved in methanol, and the solution is heated.

Preferably, the solution is heated to a temperature of about 60° C. toabout 70°, preferably about 65° C. Preferably, the solution ismaintained at this temperature for about 0.5 hours to about 2 hours,preferably for about 1 hours.

The heated solution is then cooled and maintained for overnight.Preferably, the heated solution is cooled and maintained at atemperature of about 5° C.

Form AE can then be recovered from the suspension by filtering theprecipitated crystalline form and washing it with methanol.

Form AE can also be prepared by a process comprising providing asolution of dasatinib in DMSO, transforming the solution into a firstsuspension and combining the first suspension with methanol providing asecond suspension comprising said crystalline form.

Preferably, dasatinib is dissolved in DMSO at a temperature of about 40°C. to about 60° C., preferably of about 50° C. providing the solution.The solution is transformed to the first suspension, preferably, byheating the solution to a temperature of about 60° C. to about 70° C.,preferably to about 65° C.

Preferably, methanol is added to the first suspension providing thesecond suspension.

The second suspension is then cooled. Preferably, the cooling is to atemperature of about 0° C. to about 5° C.

Form AE can then be recovered by filtering the second suspension andwashing the filtered precipitate with methanol.

In another embodiment, the present invention encompasses an ethylacetatesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 8.9, 11.8, 12.4, 16.1, 22.3 and 25.4±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 31, and a combinationthereof. This form can be designated as form AF.

In a preferred embodiment, the present invention encompasses anethylacetate solvate of dasatinib designated Form AF characterized by aPXRD pattern having peaks at about 8.9 and 12.4±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 6.0, 11.8, 16.1, 22.3and 25.4±0.2 degrees 2-theta.

The above ethylacetate solvate of dasatinib designated Form AF can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 8.9, 11.8, 16.1 and 25.4±0.2degrees 2-theta; a powder XRD pattern with peaks at about 8.9, 11.8,12.4, 16.1 and 22.3±0.2 degrees 2-theta; and a weight loss on drying ofabout 9% to about 11% by weight, preferably about 10% by weight, asmeasured by TGA

Form AF can be prepared by a process comprising suspending form A21 ofdasatinib in ethylacetate.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably about 25° C.

Form AF can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AF is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a 2-pentanolesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.6, 11.3, 17.1, 17.3 and 21.9±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 32, and a combination thereof.This form can be designated as form AG.

In a preferred embodiment, the present invention encompasses a2-pentanole solvate of dasatinib designated Form AG characterized by aPXRD pattern having peaks at about 5.6, 11.3, 17.1, 17.3 and 21.9±0.2degrees 2-theta.

The above 2-pentanole solvate of dasatinib designated Form AG can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.6, 11.3, 17.1 and 17.3±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.6, 11.3,17.1 and 21.9±0.2 degrees 2-theta; and a weight loss on drying in twosteps, one of about 52% and the second of about 6%, as measured by TGA.

Form AG can be prepared by a process comprising suspending form A21 ofdasatinib in 2-pentanole.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably to about 25° C.

Form AG can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AG is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib characterized by data selected from thegroup consisting of: a PXRD pattern having any 3 peaks selected from thelist consisting of: 12.1, 17.3, 18.3, 24.5, 24.7 and 26.5±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 33, and combinationthereof. This form can be designated as form AI.

In a preferred embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib designated Form AI characterized by aPXRD pattern having peaks at about 18.3 and 24.7±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 12.1, 17.3, 24.5, and26.5±0.2 degrees 2-theta.

The above dimethyl carbonate solvate of dasatinib designated Form A1 canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 12.1, 17.3, 18.3 and 26.5±0.2degrees 2-theta; a powder XRD pattern having a double peak at about 24.5and 24.7±0.2 degrees 2-theta; and a weight loss on drying in two stepsone of about 66% and the second of about 13%, as measured by TGA.

Form AI can be prepared by a process comprising suspending form A21 ofdasatinib in dimethyl carbonate at a temperature of about 50° C. for aperiod of about 6 hours, and cooling the suspension to a temperature ofabout of 25° C. for a period of about overnight.

Form AI can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AI is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses anisopropylacetate solvate of dasatinib characterized by data selectedfrom the group consisting of: a PXRD pattern having any 3 peaks selectedfrom the list consisting of: 5.8, 10.3, 12.3, 17.3, 21.9 and 24.4±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 34, and acombination thereof. This form can be designated as form AJ.

In a preferred embodiment, the present invention encompasses anisopropylacetate solvate of dasatinib designated Form AJ characterizedby a PXRD pattern having peaks at about 12.3 and 17.3±0.2 degrees2-theta and any 3 peaks selected from the list consisting of: 5.8, 10.3,21.9 and 24.4±0.2 degrees 2-theta.

The above isopropylacetate solvate of dasatinib designated Form AJ canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 10.3, 12.3, 17.3 and 21.9±0.2degrees 2-theta; a powder XRD pattern with peaks at about 5.8, 12.3,21.9 and 24.4±0.2 degrees 2-theta; and a weight loss on drying in twosteps one of about 6% and the second of about 4%, as measured by TGA.

Form AJ can be prepared by a process comprising suspending form A21 ofdasatinib in isopropylacetate.

Preferably, the suspension is heated to a temperature of about 40° C. toabout 60° C., preferably to about 50° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

Form AJ can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AJ is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses adichloromethane solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.9, 7.1, 11.8, 14.4, 14.8, 18.3 and 22.9±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 36, and acombination thereof. This form can be designated as form AL.

In a preferred embodiment, the present invention encompasses adichloromethane solvate of dasatinib designated Form AL characterized bya PXRD pattern having peaks at about 7.1 and 14.4±0.2 degrees 2-thetaand any 3 peaks selected from the list consisting of: 5.9, 11.8, 14.8,18.3 and 22.9±0.2 degrees 2-theta.

The above dichloromethane solvate of dasatinib designated Form AL can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 7.1, 14.4, 18.3 and 22.9±0.2degrees 2-theta; a powder XRD pattern with peaks at about 7.1, 11.8,14.4, 14.8 and 18.3±0.2 degrees 2-theta; and a weight loss on drying ofabout 10% to about 12% by weight, preferably of about 11% by weight, asmeasured by TGA

Form AL can be prepared by a process comprising suspending form A21 ofdasatinib in dichloromethane.

Preferably, the suspension is heated to a temperature of about 25° C. toabout 40° C., preferably to about 30° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 10° C. to about 25° C., preferably to about 25° C.

Form AL can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AL is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a methylformatesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 6.0, 7.1, 11.9, 14.3, 16.0, 24.2 and 25.1±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 37, and a combinationthereof. This form can be designated as form AM.

In a preferred embodiment, the present invention encompasses amethylformate solvate of dasatinib designated Form AM characterized by aPXRD pattern having peaks at about 7.1 and 16.0±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 6.0, 11.9, 14.3, 24.2and 25.1±0.2 degrees 2-theta.

The above methylformate solvate of dasatinib designated Form AM can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.1, 7.1, 11.9, 14.3 and 16.0±0.2degrees 2-theta; a powder XRD pattern with peaks at about 7.1, 14.3,16.0, 24.2 and 25.1±0.2 degrees 2-theta; and a weight loss on drying intwo steps, one of about 3% and the second of about 8%, as measured byTGA.

Form AM can be prepared by a process comprising suspending form A21 ofdasatinib in methylformate.

Preferably, the suspension is heated to a temperature of about 25° C. toabout 40° C., preferably of about 30° C. Preferably, the suspension ismaintained at this temperature for about 4 hours to about 12 hours,preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 10° C. to about 25° C., preferably to about 25° C.

Form AM can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, form AM is maintained at atmospheric pressure, preferably,at about room temperature, preferably, for a period of overnight.

In another embodiment, the present invention encompasses a tert-butanolsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 11.8, 12.0, 15.0, 17.7, 18.1 and 26.3±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 38, and a combinationthereof. This form can be designated as form AN.

In a preferred embodiment, the present invention encompasses atert-butanol solvate of dasatinib designated Form AN characterized by aPXRD pattern having peaks at about 11.8 and 18.1±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 5.9, 12.0, 15.0, 17.7,and 26.3±0.2 degrees 2-theta.

The above tert-butanol solvate of dasatinib designated Form AN can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 11.8, 12.0, 17.7, 18.1 and26.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 5.9,12.0, 15.0, 17.7 and 18.1±0.2 degrees 2-theta; and a weight loss ondrying of about 12% to about 15% by weight, preferably of about 13% byweight, as measured by TGA.

Form AN can be prepared by a process comprising suspending form A21 ofdasatinib in tert-butanol.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably to about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably to about 25° C.

Form AN can then be recovered from the cooled suspension by evaporatingthe solvent. Preferably, the solvent is removed at about roomtemperature. Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AN atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In another embodiment, the present invention encompasses adimethoxyethane solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 6.1, 12.1, 15.3, 21.0, 23.1 and 24.4±0.2 degrees2-theta, a powder XRD pattern as depicted in FIG. 39, and a combinationthereof. This form can be designated as form AP.

In a preferred embodiment, the present invention encompasses adimethoxyethane solvate of dasatinib designated Form AP characterized bya PXRD pattern having peaks at about 21.0 and 24.4±0.2 degrees 2-thetaand any 3 peaks selected from the list consisting of: 6.1, 12.1, 15.3and 23.1±0.2 degrees 2-theta.

The above dimethoxyethane solvate of dasatinib designated Form AP can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.1, 12.1, 15.3, 21.0 and24.4±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 6.1,15.3, 21.0, 23.1 and 24.4±0.2 degrees 2-theta; and a weight loss ondrying of about 10% to about 12% by weight, preferably about 11% byweight, as measured by TGA.

Form AP can be prepared by a process comprising drying crystallinedasatinib form AB.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In another embodiment, the present invention encompasses a MEK solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 5.9, 12.2, 14.7, 15.1, 21.7, 24.5 and 24.9±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 40, and a combination thereof.This form can be designated as form AQ.

In a preferred embodiment, the present invention encompasses a MEKsolvate of dasatinib designated Form AQ characterized by a PXRD patternhaving peaks at about 14.7 and 24.9±0.2 degrees 2-theta and any 3 peaksselected from the list consisting of: 5.9, 12.2, 15.1, 21.7 and 24.5±0.2degrees 2-theta.

The above MEK solvate of dasatinib designated Form AQ can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.9, 12.2, 14.7, 21.7 and 24.5±0.2degrees 2-theta; a powder XRD pattern with peaks at about 12.2, 15.1,21.7, 24.5 and 24.9±0.2 degrees 2-theta; and a weight loss on drying ofabout 9% to about 11% by weight, preferably about 10% by weight, asmeasured by TGA.

Form AQ can be prepared by a process comprising suspending form A21 ofdasatinib in MEK.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably to about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably to about 25° C.

Form AQ can then be recovered from the cooled suspension by evaporatingthe solvent. Preferably, the solvent is removed at about roomtemperature. Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AQ atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In another embodiment, the present invention encompasses amonochlorobenzene solvate of dasatinib characterized by data selectedfrom the group consisting of: a PXRD pattern having any 3 peaks selectedfrom the list consisting of: 6.2, 12.4, 15.8, 18.7, 23.6 and 26.8±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 41, andcombination thereof. This form can be designated as form AR.

In a preferred embodiment, the present invention encompasses amonochlorobenzene solvate of dasatinib designated Form AR characterizedby a PXRD pattern having peaks at about 12.4 and 15.8±0.2 degrees2-theta and any 3 peaks selected from the list consisting of: 6.2, 18.7,23.6 and 26.8±0.2 degrees 2-theta.

The above monochlorobenzene solvate of dasatinib designated Form AR canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 6.2, 12.4, 15.8, 18.7 and23.6±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 12.4,15.8, 18.7, 23.6 and 26.8±0.2 degrees 2-theta; and a weight loss ondrying in two steps, one of about 30% and the second of about 6%, asmeasured by TGA.

Form AR can be prepared by a process comprising suspending form A21 ofdasatinib in monochlorobenzene at a temperature of about 50° C. for aperiod of about 6 hours, and cooling the suspension to a temperature ofabout of 25° C. for a period of about overnight.

Form AR can then be recovered from the cooled suspension by evaporatingthe solvent. Preferably, the solvent is removed at about roomtemperature. Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AR atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In another embodiment, the present invention encompasses a PGME solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 5.7, 11.5, 17.0, 17.4, 22.0, 23.1 and 24.3±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 42, and a combination thereof.This form can be designated as form AS.

In a preferred embodiment, the present invention encompasses a PGMEsolvate of dasatinib designated Form AS characterized by a PXRD patternhaving peaks at about 11.5 and 23.1±0.2 degrees 2-theta and any 3 peaksselected from the list consisting of: 5.7, 17.0, 17.4, 22.0 and 24.3±0.2degrees 2-theta.

The above PGME solvate of dasatinib designated Form AS can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.7, 11.5, 17.0, 17.4 and 23.1±0.2degrees 2-theta; a powder XRD pattern with peaks at about 11.5, 17.0,22.0, 23.1 and 24.4±0.2 degrees 2-theta; and a weight loss on drying ofabout 12% to about 15% by weight, preferably of about 14% by weight, asmeasured by TGA.

Form AS can be prepared by a process comprising suspending form A21 ofdasatinib in PGME.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably of about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably to about 25° C.

Form AS can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AS atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In another embodiment, the present invention encompasses a cyclopentylmethyl ether solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 5.8, 14.6, 17.5, 21.1, 22.4, 23.9 and 24.3±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 44, and acombination thereof. This form can be designated as form AU.

In a preferred embodiment, the present invention encompasses acyclopentyl methyl ether solvate of dasatinib designated Form AUcharacterized by a PXRD pattern having peaks at about 17.5 and 23.9±0.2degrees 2-theta and any 3 peaks selected from the list consisting of:5.8, 14.6, 21.1, 22.4 and 24.3±0.2 degrees 2-theta.

The above cyclopentyl methyl ether solvate of dasatinib designated FormAU can be further characterized by data selected from the groupconsisting of: a powder XRD pattern with peaks at about 14.6, 17.5,21.1, 22.4 and 24.3±0.2 degrees 2-theta; a powder XRD pattern with peaksat about 5.8, 14.6, 21.1, 22.4 and 23.9±0.2 degrees 2-theta; and aweight loss on drying by TGA of about 9% to about 11% by weight,preferably about 10% by weight.

Form AU can be prepared by a process comprising suspending form A21 ofdasatinib in cyclopentyl methyl ether.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably of about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

Form AU can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AU atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In another embodiment, the present invention encompasses a MTBE solvateof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having any 3 peaks selected from the list consistingof: 5.8, 10.0, 19.2, 19.6, 22.4, 25.7 and 26.1±0.2 degrees 2-theta, apowder XRD pattern as depicted in FIG. 45, and a combination thereof.This form can be designated as form AV.

In a preferred embodiment, the present invention encompasses a MTBEsolvate of dasatinib designated Form AV characterized by a PXRD patternhaving peaks at about 10.0 and 22.4±0.2 degrees 2-theta and any 3 peaksselected from the list consisting of: 5.8, 19.2, 19.6, 25.7 and 26.1±0.2degrees 2-theta.

The above MTBE solvate of dasatinib designated Form AV can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.8, 10.0, 19.6, 25.7 and 26.1±0.2degrees 2-theta; a powder XRD pattern with peaks at about 10.0, 19.2,22.4, 25.7 and 26.1±0.2 degrees 2-theta; and a weight loss on drying byTGA of about 7% to about 9% by weight, preferably of about 8% by weight.

Form AV can be prepared by a process comprising suspending form A21 ofdasatinib in MTBE.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably of about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

Form AV can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AV atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In another embodiment, the present invention encompasses an amylalcoholsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.6, 10.4, 11.2, 21.7, 23.1 and 26.1±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 46, and a combination thereof.This form can be designated as form AH.

In a preferred embodiment, the present invention encompasses anamylalcohol solvate of dasatinib designated Form AH characterized by aPXRD pattern having peaks at about 10.4 and 11.2±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 5.6, 21.7, 23.1 and26.1±0.2 degrees 2-theta.

The above amylalcohol solvate of dasatinib designated Form AH can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.6, 10.4, 21.7, 23.1 and26.1±0.2 degrees 2-theta; a powder XRD pattern having a double peak atabout 16.8 and 17.0±0.2 degrees 2-theta; and a weight loss on drying intwo steps one of about 72% and the second of about 3%, as measured byTGA.

Form AH can be prepared by a process comprising suspending form A21 ofdasatinib in amylalcohol.

Preferably, the process further comprises heating the suspension to atemperature of about 40° C. to about 60° C., preferably of about 50° C.Preferably, the suspension is maintained at this temperature for about 4hours to about 12 hours, preferably for about 6 hours.

The heated suspension is then cooled and maintained for overnight.Preferably, the heated suspension is cooled and maintained at atemperature of about 15° C. to about 30° C., preferably of about 25° C.

Form AH can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed at about room temperature.Preferably, the solvent is removed at atmospheric pressure.

Preferably, the removal of the solvent is done by maintaining form AH atatmospheric pressure, preferably, at about room temperature, preferably,for a period of overnight.

In one embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib characterized by data selected from thegroup consisting of: a PXRD pattern having any 3 peaks selected from thelist consisting of: 12.5, 13.6, 16.2, 21.7 and 25.6±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 47, and a combination thereof.This form can be designated as form AY.

In a preferred embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib characterized by a PXRD pattern havingpeaks at about 12.5, 13.6, 16.2, 21.7 and 25.6±0.2 degrees 2-theta.

The above dimethyl carbonate solvate of dasatinib designated Form AY canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 13.6, 16.2, 21.7 and 25.6±0.2degrees 2-theta; a powder XRD pattern with peaks at about 12.5, 13.6,16.2 and 25.6±0.2 degrees 2-theta; and a weight loss on drying by TGA ofabout 8% to about 10% by weight, preferably about 9% by weight.

Form AY can be prepared by a process comprising drying dasatinib formAI.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In one embodiment, the present invention encompasses an ethylene glycolsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 7.5, 12.3, 14.7 and 16.4±0.2 degrees 2-theta, a powderXRD pattern as depicted in FIG. 48, and a combination thereof. This formcan be designated as form AW.

In a preferred embodiment, the present invention encompasses an ethyleneglycol solvate of dasatinib characterized by a PXRD pattern having peaksat about 7.5, 12.3, 14.7 and 16.4±0.2 degrees 2-theta.

The above ethylene glycol solvate of dasatinib designated Form AW can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 7.5, 12.3 and 16.4±0.2 degrees2-theta; a powder XRD pattern with peaks at about 7.5, 14.7 and 16.4±0.2degrees 2-theta; and a weight loss on drying by TGA of about 85% toabout 90%, preferably about 90% by weight.

The above ethylene glycol solvate of dasatinib designated Form AW maycontain traces of amorphous dasatinib.

Form AW can be prepared by a process comprising drying dasatinib formAK.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In one embodiment, the present invention encompasses an anhydrous formof dasatinib characterized by data selected from the group consistingof: a PXRD pattern having peaks at about 5.1 and 10.2±0.2 degrees2-theta and any 3 peaks selected from the list consisting of: 5.1, 6.0,10.2, 20.3, 20.5, 23.5 and 26.8±0.2 degrees 2-theta, a powder XRDpattern as depicted in FIG. 97, and a combination thereof. This form canbe designated as form BA.

The above anhydrous form of dasatinib designated Form BA can be furthercharacterized by data selected from the group consisting of: a powderXRD pattern with peaks at about 5.1, 6.0, 10.2, 23.5 and 26.8±0.2degrees 2-theta; a powder XRD pattern having a double peak at about 20.3and 20.5±0.2 degrees 2-theta; and a weight loss on drying by TGA ofabout 2% by weight or less.

Form BA can be prepared by a process comprising drying amorphous form ofdasatinib.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In one embodiment, the present invention encompasses a monochlorobenzenesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.9, 12.0, 15.3, 17.9, 24.3 and 26.2±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 98, and a combination thereof.This form can be designated as form BB.

In a preferred embodiment, the present invention encompasses amonochlorobenzene solvate of dasatinib designated Form BB andcharacterized by a PXRD pattern having peaks at about 15.3 and 26.2±0.2degrees 2-theta and any 3 peaks selected from the list consisting of:5.9, 12.0, 17.9 and 24.3±0.2 degrees 2-theta.

The above monochlorobenzene solvate of dasatinib designated Form BB canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 5.9, 12.0, 15.3, 17.9 and24.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 12.0,15.3, 17.9, 24.3 and 26.2±0.2 degrees 2-theta; and a weight loss ondrying by TGA of about 9% to about 11% by weight, preferably about 10%by weight.

Form BB can be prepared by a process comprising drying dasatinib formAR, dasatinib form BJ, or mixtures thereof.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In one embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib characterized by data selected from thegroup consisting of: a PXRD pattern having any 3 peaks selected from thelist consisting of: 12.0, 16.7, 19.1, 21.0, 21.6, 23.0 and 24.5±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 109, and acombination thereof. This form can be designated as form BD.

In a preferred embodiment, the present invention encompasses a dimethylcarbonate solvate of dasatinib designated Form BD characterized by aPXRD pattern having peaks at about 16.7 and 21.6±0.2 degrees 2-theta andany 3 peaks selected from the list consisting of: 12.0, 19.1, 21.0, 23.0and 24.5±0.2 degrees 2-theta.

The above dimethyl carbonate solvate of dasatinib designated Form BD canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 16.7, 19.1, 21.0, 23.0 and24.5±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 12.0,19.1, 21.0, 21.6 and 24.5±0.2 degrees 2-theta; and a weight loss ondrying by TGA of about 1.3% by weight at a temperature of about 25° C.to about 67° C.

Form BD can be prepared by a process comprising suspending form A21 ofdasatinib in dimethyl carbonate at a temperature of about 50° C. for aperiod of about 4 hours, and cooling the suspension to a temperature ofabout of 25° C. for a period of about 3 days.

Form BD can then be recovered from the suspension by evaporating thesolvent, and drying. Preferably, the solvent is removed for a period ofabout 2 days.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In one embodiment, the present invention encompasses a methyl isopropylketone (“MIPK”) solvate of dasatinib characterized by data selected fromthe group consisting of: a PXRD pattern having any 3 peaks selected fromthe list consisting of: 10.1, 12.1, 12.7, 17.5, 17.9, 19.9 and 25.9±0.2degrees 2-theta, a powder XRD pattern as depicted in FIG. 110, and acombination thereof. This form can be designated as form BG.

In a preferred embodiment, the present invention encompasses methylisopropyl ketone (“MIPK”) solvate of dasatinib characterized by a PXRDpattern having peaks at about 10.1 and 12.7±0.2 degrees 2-theta and any3 peaks selected from the list consisting of: 12.1, 17.5, 17.9, 19.9 and25.9±0.2 degrees 2-theta.

The above methyl isopropyl ketone solvate of dasatinib designated FormBG can be further characterized by data selected from the groupconsisting of: a powder XRD pattern with peaks at about 12.1, 12.7,17.9, 19.9 and 25.9±0.2 degrees 2-theta; a powder XRD pattern with peaksat about 10.1, 12.1, 17.5, 19.9 and 25.9±0.2 degrees 2-theta; and aweight loss on drying in three steps, one of about 2% by weight, thesecond of about 7% by weight and the third of about 6% by weight asmeasured by TGA.

Form BG can be prepared by a process comprising suspending form A21 ofdasatinib in methyl isopropyl ketone (“MIPK”) at a temperature of about50° C. for a period of about 4 hours, and cooling the suspension to atemperature of about of 25° C. for a period of about 3 days.

Form BG can then be recovered from the suspension by evaporating thesolvent, and drying. Preferably, the solvent is removed over a period ofabout 2 days.

Preferably, drying is done at a temperature of about 50° C. to about 60°C., preferably of about 55° C., preferably, for a period of overnight.

In one embodiment, the present invention encompasses a monochlorobenzenesolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having any 3 peaks selected from the listconsisting of: 5.6, 10.3, 11.3, 17.3, 22.3 and 26.1±0.2 degrees 2-theta,a powder XRD pattern as depicted in FIG. 111, and a combination thereof.This form can be designated as form BJ.

In a preferred embodiment, the present invention encompasses amonochlorobenzene solvate of dasatinib characterized by a PXRD patternhaving peaks at about 10.3 and 17.3±0.2 degrees 2-theta and any 3 peaksselected from the list consisting of: 5.6, 11.3, 22.3 and 26.1±0.2degrees 2-theta.

The above monochlorobenzene solvate of dasatinib designated Form BJ canbe further characterized by data selected from the group consisting of:a powder XRD pattern with peaks at about 5.6, 10.3, 17.3, 22.3 and26.1±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 5.6,10.3, 11.3, 17.3 and 26.1±0.2 degrees 2-theta; and a weight loss ondrying by TGA of about 73% by weight.

Form BJ can be prepared by a process comprising suspending form A21 ofdasatinib in monochlorobenzene at a temperature of about 50° C. for aperiod of about 4 hours, and cooling the suspension to a temperature ofabout of 25° C. for a period of about 3 days.

Form BJ can then be recovered from the suspension by evaporating thesolvent. Preferably, the solvent is removed over a period of about 2days.

In one embodiment, the present invention encompasses a glycerol formalsolvate of dasatinib characterized by a PXRD pattern having any 3 peaksselected from the list consisting of: 5.9, 11.8, 17.8, 18.6, 20.5, 23.8and 24.3±0.2 degrees 2-theta.

In one embodiment, the present invention encompasses a glycerol formalsolvate of dasatinib characterized by data selected from the groupconsisting of: a PXRD pattern having peaks at about 17.8 and 23.8±0.2degrees 2-theta and any 3 peaks selected from the list consisting of:5.9, 11.8, 17.8, 18.6, 20.5, 23.8 and 24.3±0.2 degrees 2-theta, a powderXRD pattern as depicted in FIG. 125, and combination thereof. This formcan be designated as form BL.

The above glycerol formal solvate of dasatinib designated Form BL can befurther characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 5.9, 17.8, 18.6, 23.8 and24.3±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 11.8,17.8, 18.6, 20.5 and 23.8±0.2 degrees 2-theta; and a weight loss ondrying of about 15% to about 17% by weight, preferably about 16% byweight, by TGA in the temperature range 100-210° C.

Form BL of dasatinib can be prepared by a process comprisingcrystallizing dasatinib from glycerol formal.

The crystallization comprises providing a solution of dasatinib inglycerol formal, and precipitating said crystalline form to obtain asuspension.

Preferably, the solution is provided by combining dasatinib and glycerolformal, and heating the combination. Preferably, heating is to about120° C. to about 140° C., preferably to about 130° C.

Preferably, precipitation is obtained by cooling the solution.Preferably, cooling is to a temperature of about 10° C. to about 25° C.,preferably about 20° C.

The process for preparing form BL of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension, washing, and drying.

In one embodiment, the present invention encompasses dasatinibcharacterized by data selected from the group consisting of: a PXRDpattern having peaks at about 6.4 and 14.0±0.2 degrees 2-theta and any 3peaks selected from the list consisting of: 6.4, 12.7, 14.0, 19.0, 21.7and 25.0±0.2 degrees 2-theta, a powder XRD pattern as depicted in FIG.131, and combination thereof. This form can be designated as form BM.

The above dasatinib designated Form BM can be further characterized bydata selected from the group consisting of: a powder XRD pattern withpeaks at about 6.4, 12.7, 14.0, 19.0 and 25.0±0.2 degrees 2-theta; apowder XRD pattern with peaks at about 6.4, 12.7, 14.0, 19.0 and21.7±0.2 degrees 2-theta; and a weight loss on drying about 1% by weightor less by TGA.

In addition, crystalline Dasatinib Form BM has less than about 15% byweight, preferably, less about than 10% by weight, more preferably, lessthan about 5% by weight of crystalline Dasatinib forms N-6 and H1-7 ormixtures thereof.

Typically, the amount of form N-6 in form BM is measured by PXRD usingany peaks selected from the group consisting of peaks at: 6.9, 17.3,21.1 and 24.4 deg±0.2 degrees 2-theta and the amount of form H1-7 inform BM is measured by PXRD using any peaks selected from the groupconsisting of peaks at: 4.6, 9.2, 12.3, 15.2, 17.9, 18.4, 19.6 and 21.2deg±0.2 degrees 2-theta.

Form BM of dasatinib can be prepared by a process comprising providing asolution of dasatinib in methanol, and precipitating said crystallineform by cooling to a temperature of about 0° C. to about −15° C. toobtain a suspension.

Preferably, the solution is provided by combining dasatinib andmethanol, and heating the combination. Preferably, heating is to about60° C. to about 70° C., preferably to about 64° C.-65° C.

Preferably, precipitation is obtained by cooling the solution.Preferably, cooling is to a temperature of about 0° C. to about −115° C.

The process for preparing form BM of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension, and drying.

The present invention also provides a process for preparing crystallineform H1-7 comprising reacting compound 1, N-(2-hydroxyethyl)piperazine,and N-ethyldiisopropylamine in DMF to obtain a solution comprisingdasatinib, adding water to obtain a precipitate, and cooling to obtainsaid crystalline form.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMF is doneat a temperature of about 90° C. to about 100° C., more preferably, at atemperature of about 100° C. Preferably, the reaction is done for about2.5 hours to about 4 hours, more preferably, for about 2.5 hours.

Preferably, water is added at a temperature of about 100° C.

Preferably, the cooling is to a temperature of about 25° C. to about 10°C., more preferably, of about room temperature.

The process for preparing Form H1-7 form of dasatinib can furthercomprise recovering said form. The recovery can be done for example, byfiltering the suspension and drying.

In another embodiment, the present invention encompasses a purecrystalline form T1E2-1 of dasatinib, characterized by a powder XRDpattern as depicted in FIG. 106.

As used herein, the term “pure crystalline” in reference to crystallineform T1E2-1 of Dasatinib corresponds to crystalline form T1E2-1 ofDasatinib containing less than about 5% by weight, preferably, less than2% by weight, more preferably, less than about 1% by weight ofcrystalline Dasatinib diethanolate.

The content of crystalline dasatinib diethanolate in crystalline T1E2-1is measured by PXRD using the peak at about 6.0°±0.2 degrees2-theta-theta.

The pure crystalline form T1E2-1 can be prepared by a process comprisingmixing crystalline dasatinib selected from the group consisting ofcrystalline form K2, crystalline form A2, and mixtures thereof withethanol.

Preferably, mixing is done at about room temperature. Preferably, theobtained mixture is stirred. Preferably, stirring is done for about 2hours to about 6 hours, preferably for about 4 hours.

The process for preparing pure crystalline form T1E2-1 can furthercomprise recovering said form. The recovery can be done for example, byfiltering the suspension.

The present invention also provides another process for preparing purecrystalline form T1E2-1 providing a solution of dasatinib in a mixtureof ethanol and water, and precipitating said crystalline form to obtaina suspension.

Preferably, the solution is provided by suspending dasatinib in ethanol,heating the suspension, and adding water to obtain the said solution.Preferably, the suspended Dasatinib is crystalline form L2 of Dasatinib,i.e., Dasatinib 2-butanol, crystalline form BU-2, i.e., n-butanolsolvate or crystalline Dasatinib n-propanolate.

Preferably, the heating is to a temperature of about 70° C. to about 90°C., preferably about 80° C.

Optionally, the solution can be seeded prior to precipitation of thecrystalline form. Preferably, when the starting material is form BU-2,the obtained solution is seedes with anhydrous Dasatinib. Preferably,the solution is seeded with N-6 anhydrous dasatinib.

Preferably, the precipitation is done by cooling the solution to atemperature of less than about 5° C. to about 0° C., more preferably, toabout 5° C. to about 0° C.

The process for preparing pure crystalline form T1E2-1 can furthercomprise recovering said form. The recovery can be done for example, byfiltering the suspension and drying.

The present invention provides an additional process for preparing purecrystalline form T1E2-1 comprising suspending dasatinib form A21 in amixture comprising ethanol and water.

Preferably, dasatinib form A21 is suspended in said solvent mixture at atemperature of about 25° C. to about 75° C., more preferably, at about75° C.

Preferably, the suspension is maintained at the above mentionedtemperature for about 0.5 hours to about 2 hours, preferably about 1hour.

The process for preparing pure crystalline form T1E2-1 can furthercomprise recovering said form. The recovery can be done for example, bycooling the heated suspension and filtering the suspension.

Preferably, the cooling is to a temperature of about 5° C. to about −10°C., preferably to about 5° C.

The present invention also provides a process for preparing crystallineform T1E2-1 comprising crystallizing dasatinib from a mixture comprisingthe compound of formula 1, N-(2-hydroxyethyl) piperazine,N-ethyldiisopropylamine and a mixture of DMSO and ethanol.

The crystallization comprises reacting compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO toobtain a solution comprising dasatinib, adding ethanol, andprecipitating said crystalline form to obtain a suspension.

Preferably, the reaction of a mixture of compound 1,N-(2-hydroxyethyl)piperazine, and N-ethyldiisopropylamine in DMSO isdone at a temperature of about 40° C. to about 150° C., more preferably,at about 40° C. to about 100° C., most preferably, at about 60° C. toabout 80° C. Preferably, the reaction is done for about 1 hour to about2 hours depending on the reaction temperature.

Preferably, ethanol is added at a temperature of about 60° C. to about80° C., providing a second solution. Optionally, water can be addedafter adding ethanol, providing a third solution. Preferably, water isadded at a temperature of about 60° C. to about 80° C.

Preferably, the cooling is to a temperature of about 25° C. to about 10°C., more preferably, of about room temperature.

The process for preparing form T1E2-1 of dasatinib can further compriserecovering said form. The recovery can be done for example, by filteringthe suspension and drying.

The present invention also provides a process for preparing crystallineform N-6 comprising dying form P of dasatinib.

Preferably, drying is done at a temperature of about 200° C.

The present invention provides an additional process for preparing purecrystalline form N-6 comprising heating form A3 of dasatinib.

Preferably, heating is done to a temperature of about 200° C. to about210° C., more preferably, at 208° C.

Preferably, drying is done for a period of about 15 minutes.

The above forms of dasatinib can be used to prepare pharmaceuticalcompositions. Preferably, the formulated polymorph is selected from thegroup consisting of: crystalline forms A3, A21, B, C and amorphous, morepreferably, forms A3, A21 and B.

In yet another embodiment, the invention encompasses a pharmaceuticalcomposition comprising at least one of the above described polymorphs ofdasatinib, and at least one pharmaceutically acceptable excipient.

The present invention also encompasses a pharmaceutical compositioncomprising at least one of the above described polymorphs of dasatinibprepared according to the processes of the present invention, and atleast one pharmaceutically acceptable excipient.

In another embodiment, the invention encompasses a process for preparinga pharmaceutical composition comprising at least one of theabove-described polymorphs of dasatinib, and at least onepharmaceutically acceptable excipient.

In another embodiment, the invention encompasses a method of treatingchronic yelogenous leukemia after imatinib treatemant, and Philadelphiachromosome-positive acute lymphoblastic leukemia comprisingadministering the pharmaceutical composition comprising at least one ofthe above described polymorphs of dasatinib to a patient in needthereof.

One embodiment of the invention provides the use of the abovecrystalline forms of dasatinib of the present invention for themanufacture of a pharmaceutical composition.

EXAMPLES

PXRD

XRD diffraction was performed on X-Ray powder diffractometer: PhilipsX'pert Pro powder diffractometer, CuK_(α) radiation, λ=1.5418 Å.X'Celerator detector active length (2 theta)=2.122°, laboratorytemperature 22-25° C. Zero background sample holders. Prior to analysisthe samples were gently ground by means of mortar and pestle in order toobtain a fine powder. The ground sample was adjusted into a cavity ofthe sample holder and the surface of the sample was smoothed by means ofa cover glass.

A silicon internal standard can be used to calibrate peak positions andto eliminate an effect of a sample preparation. The internal standardpossesses a diffraction with defined position at 28.44 degrees 2-theta.The internal standard can be mixed with a sample, PXRD is then acquiredand the current position of the aforementioned internal standarddiffraction peak is determined. The difference between the currentposition of the diffraction and its nominal value of 28.44 degrees2-theta is calculated. The current positions of all relevant samplepeaks are then re-calculated by means of the difference to obtain truepositions of the sample diffractions.

¹³C NMR

The CP/MAS ¹³C NMR measurements were made at Bruker Avance 500 NMR US/WBspectrometer in 4-mm ZrO2 rotor. Magic angle spinning (MAS) speed was 10kHz. As used herein, the term “¹³C NMR chemical shifts” refers to theshifts measured under above specified conditions, however, these shiftscan slightly differ instrument to instrument and can be shifted eitherupfield or downfield due to the different instrumental setup andcalibration used. Nevertheless the sequence of individual peaks remainsidentical.

DSC

DSC measurements were performed on Differential Scanning CalorimeterDSC823e (Mettler Toledo). A1 crucibles 40 μl with PIN were used forsample preparation. Usual weight of sample was 1.5-3.5 mg.

Program: temperature range 25° C.-250° C., 10° C./min.

Water Content by KF

Water content was determined by Karl Fischer titrator TITRANDO 841,software Tiamo 1.1 (Metrohm). Solution used for determination: HydranalComposite 2 (Riedel de Haen). Sampling: 100 mg, 2 repeats.

TGA

DSC measurements were performed on Differential Scanning CalorimeterDSC823e (Mettler Toledo). Alumina crucibles 70 μl were used for samplepreparation. Usual weight of sample was 7-13 mg.

Program: temperature range 25° C.-250° C., 10° C./min; or 25° C.-350°C., 10° C./min.

GC

Residual solvents were determined by gas chromatography using head-spacesampling. Headspace instrument HP7694 together with Gas chromatographA6890 equipped with FID detector (Agilent technologies).

Crystal Structure Determination

Powder diffraction pattern was measured using synchrotron radiation atwavelength 0.80809(8) Å. Data were collected from 4 to 41 degrees 2thetaat 15 degrees per minute, thus 3 minute per scan, step size 0.004degrees. Crystal structure determination from powder diffraction datawas solved using FOX program.

MIBK and Pyridine:

Sample amount 50.0 mg with 0.5 ml of N-Methylpyrrolidone is mixed in20-ml headspace vial, after equilibration (30 min.) in the headspaceoven (80° C.) 1 ml of vapour phase is injected into GC. GC column:Equity-5: 30 m×0.53 mm ID×5 μm (5%—Phenylmethylpolysiloxane); Injectortemperature: 200° C., split 1:4; FID detector temperature: 250° C.; GCoven: 40° C. (10 min.)-10° C./min. to 120° C. (0 min.)-40° C./min. to220° C. (2 min.), He: 23 kPa (40° C.), 33 cm/sec., constant flow.

Other Solvents:

Sample amount 50.0 mg with 0.5 ml of N-Methylpyrrolidone is mixed in20-ml headspace vial, after equilibration (20 min.) in the headspaceoven (90° C.) 1 ml of vapour phase is injected into GC. GC column:RES-SOLV (624—Agilent for fast GC): 30 m×0.53 mm ID×1 μm(94%—methylpolysiloxane, 6%—cyanopropyl); Injector temperature: 220° C.,split 1:4; FID detector temperature: 250° C.; GC oven: 40° C. (4.2min.)—25° C./min. to 180° C. (0 min.), He: 24 kPa (40° C.), 35 cm/sec.,constant flow 4.8 ml/min.

Example 1 Procedure for the Preparation of Dasatinib Form K1

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(390.6 mg, 3 mmol) and N-ethyldiisopropylamine (0.348 ml, 2 mmol) in DMF(1 ml) was stirred at 100° C. for 2.75 h. n-propyl alcohol (10 ml) wasslowly added through a condenser and mild reflux was maintained for 10min. The reaction mixture was cooled to room temperature. The productwas filtered after 1 hour and washed with n-PrOH (2×) and dried on thefilter. Yield: 350 mg.

Example 2 Procedure for the Preparation of Dasatinib Form K2

A mixture of compound 1 (591.4 mg, 1.5 mmol),N-(2-hydroxyethyl)piperazine (390.6 mg, 3 mmol) andN-ethyldiisopropylamine (0.525 ml, 3 mmol) in DMSO (1.5 ml) was stirredat 80° C. for 1.5 h. n-propyl alcohol was added to the stirred solutionat the same temperature. The product started precipitating after theaddition of about 5 ml of n-propyl alcohol. Additional 1 ml of n-propylalcohol was added, the suspension was stirred at 80° C. for 5 min andslowly cooled to room temperature. The product was filtered off afterovernight stirring at room temperature, washed with n-propyl alcohol(2×) and dried on the filter and under reduced pressure at 40° C. for 6hours. Yield: 640 mg.

Example 3 Procedure for the Preparation of Dasatinib Form K2

A mixture of compound 1 (5.91 g, 15 mmol), N-(2-hydroxyethyl)piperazine(3.91 g, 30 mmol) and N-ethyldiisopropylamine (5.25 ml, 30 mmol) in DMSO(15 ml) was stirred at 80° C. for 60 min. n-Propyl alcohol (46 ml) wasslowly added and the temperature was maintained at 80° C. The productstarted precipitating after the given amount of n-PrOH had been added.The suspension was stirred at 80° C. for 10 min, then slowly cooled toroom temperature during 90 min and stirred at room temperature for 20min. The suspension was cooled to 10° C. and after 15 min the productwas filtered off, washed with isopropyl alcohol (3×10 ml) and dried onthe filter. Yield: 5.18 g.

Example 4 Procedure for the Preparation of Dasatinib Form B

A mixture of compound 1 (0.45 g, 1.14 mmol),N-(2-hydroxyethyl)piperazine (0.30 g, 2.30 mmol) andN-ethyldiisopropylamine (0.30 ml, 1.75 mmol) in DMSO (5 ml) was stirredat 60-65° C. for 2 h. MeOH (35 ml) was slowly added at this temperaturefollowed by H₂O (55 ml). The solution was slowly cooled to 0-5° C. Theprecipitated product was filtered off, washed with MeOH (5.0 ml) anddried on the filter. Yield: 0.42 g.

Example 5 Procedure for the Preparation of Dasatinib Form B

Dasatinib butanolate (form BU-2, 1.00 g, 2.05 mmol) was heated in amixture of ethanol (22 ml) and water (3 ml) at 75-80° C. to achievecomplete dissolution. Water was added (8 ml) at the same temperature.The solution was cooled to 70° C. and maintained at 70° C. for 1 h.Temperature was lowered from 70° C. to 5° C. during 2 h, and maintainedbetween 0-5° C. for 2 h. The product was filtered and washed withEtOH/H₂O (1:1, 2×10 ml) and dried under reduced pressure at 40° C./8 h.Yield: 0.61 g.

Example 6 Procedure for the Preparation of Dasatinib Form C

A mixture of compound 1 (0.30 g, 0.76 mmol),N-(2-hydroxyethyl)piperazine (0.49 g, 3.76 mmol) andN-ethyldiisopropylamine (0.26 ml, 1.52 mmol) in DMSO (1.5 ml) wasstirred at 40° C. for 3 hours. H₂O was slowly added at the sametemperature. The solution was slowly cooled to 0-5° C. The product wasfiltered off, washed with H₂O and dried under reduced pressure at 40° C.for 6 hours. Yield: 0.40 g.

Example 7 Procedure for the Preparation of Dasatinib Form C

A mixture of compound 1 (0.45 g, 1.14 mmol),N-(2-hydroxyethyl)piperazine (0.30 g, 2.30 mmol) andN-ethyldiisopropylamine (0.30 ml, 1.75 mmol) in DMSO (5 ml) was stirredat 60° C. for 2 h. H₂O (4 ml) was slowly added and the solution washeated at 60° C. for 30 min. The solution was slowly cooled to 0-5° C.The product was filtered off, washed with H₂O and dried on the filter.Yield: 0.39 g.

Example 8 Procedure for the Preparation of Dasatinib Form D

A mixture of compound 1 (0.21 g, 0.53 mmol),N-(2-hydroxyethyl)piperazine (0.36 g, 2.77 mmol) andN-ethyldiisopropylamine (0.17 ml, 1.0 mmol) in THF (2.5 ml) was refluxedfor 8 hours. The solution was slowly cooled to 0-5° C. The product wasfiltered off, washed with THF and dried under reduced pressure at 40° C.Yield: 0.29 g.

Example 9 Procedure for the Preparation of Dasatinib Form E

A mixture of compound 1 (0.30 g, 0.76 mmol),N-(2-hydroxyethyl)piperazine (0.52 g, 3.99 mmol) andN-ethyldiisopropylamine (0.26 ml, 1.52 mmol) in 2-methyl-THF (1.0 ml)was refluxed for 3 hours. The solution was slowly cooled to 0-5° C.Product was filtered off and washed with 2-methyl-THF and dried on thefilter. Yield: 0.45 g.

Example 10 Procedure for the Preparation of Dasatinib Form F

A mixture of compound 1 (0.30 g, 0.76 mmol),N-(2-hydroxyethyl)piperazine (0.49 g, 3.76 mmol) andN-ethyldiisopropylamine (0.26 ml, 1.52 mmol) in dioxane (1.0 ml) wasrefluxed for 3 hours. The suspension was slowly cooled to 0-5° C. Theproduct was filtered off, washed with dioxane and dried on the filter.Yield: 0.43 g.

Example 11 Procedure for the Preparation of Dasatinib Form G

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(260.4 mg, 2 mmol) and N-ethyldiisopropylamine (0.35 ml, 2 mmol) inpyridine (2 ml) was stirred at 90° C. for 3 h. Acetone (7 ml) was slowlyadded to the stirred solution through a condenser at the sametemperature maintaining a mild reflux. The suspension was cooled to roomtemperature and after 1 h the product was filtered off washed withacetone (3×) and dried on the filter. Yield: 550 mg.

Example 12 Procedure for the Preparation of Dasatinib Form G

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(260.4 mg, 2 mmol) and N-ethyldiisopropylamine (0.35 ml, 2 mmol) inpyridine (2 ml) was stirred at 100° C. for 2.5 h. Ethyl acetate (6 ml)was added through a condenser to the stirred solution at the sametemperature. The suspension was stirred and refluxed for 5 min and thenslowly cooled to room temperature. The product was filtered off after 3h and washed with ethyl acetate (2×) and dried on the filter. Yield: 660mg.

Example 13 Procedure for the Preparation of Dasatinib Form H

A mixture of compound 1 (0.34 g, 0.86 mmol),N-(2-hydroxyethyl)piperazine (0.55 g, 4.22 mmol) andN-ethyldiisopropylamine (0.29 ml, 1.7 mmol) in toluene (6 ml) wasrefluxed for 9 h. The suspension was slowly cooled to 0-5° C. Theproduct was filtered off, washed with toluene and dried on the filter,than dried under reduced pressure at 40° C. for 6 hours. Yield: 0.43 g.

Example 14 Procedure for the Preparation of Dasatinib Form I

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(260.4 mg, 2 mmol) and N-ethyldiisopropylamine (0.35 ml, 2 mmol) inpyridine (2 ml) was stirred at 100° C. for 2.5 h. Methyl isobutyl ketone(7 ml) was added to the stirred solution at the same temperature. Thesuspension was slowly cooled to room temperature. After 1 h the productwas filtered off washed with methyl isobutyl ketone (2×) and dried onthe filter. Yield: 660 mg.

Example 15 Procedure for the Preparation of Dasatinib Form J

A mixture of compound 1 (0.45 g, 1.14 mmol),N-(2-hydroxyethyl)piperazine (0.30 g, 2.30 mmol) andN-ethyldiisopropylamine (0.30 ml, 1.75 mmol) in DMSO (5 ml) was stirredat 60-65° C. for 2 hours. Acetone (20 ml) was slowly added at thistemperature followed by H₂O (30 ml). The solution was slowly cooled to0-5° C. The product was filtered off and washed with acetone (5 ml) anddried on the filter, than dried under reduced pressure at 40° C. for 6hours. Yield: 0.44 g.

Example 16 Procedure for the Preparation of Dasatinib Form J

A mixture of compound 1 (591.4 mg, 1.5 mmol),N-(2-hydroxyethyl)piperazine (390.6 mg, 3 mmol) andN-ethyldiisopropylamine (0.525 ml, 3 mmol) in DMSO (1.5 ml) was stirredat 80° C. for 1.5 h. Acetone (15 ml) was added to the stirred solutionthrough a condenser at the same temperature and refluxed. The productstarted precipitating after 3 min. The reflux continued for 5 more minand the mixture was slowly cooled to room temperature. The product wasfiltered off after 4 h, washed with acetone (3×) and dried on thefilter. Yield: 600 mg.

Example 17 Procedure for the Preparation of Dasatinib Form J (AcetoneSolvate)

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(390.6 mg, 3 mmol) and N-ethyldiisopropylamine (0.348 ml, 2 mmol) in DMF(1 ml) was stirred at 100° C. for 2.5 h. Acetone (15 ml) was slowlyadded through a condenser and mild reflux was maintained for 10 min. Thesuspension was cooled to room temperature. The product was filteredafter 1 hour and washed with acetone (3×) and dried on the filter.Yield: 360 mg.

Example 18 Procedure for the Preparation of Dasatinib Form A2

A mixture of compound 1 (591.4 mg, 1.5 mmol),N-(2-hydroxyethyl)piperazine (390.6 mg, 3 mmol) andN-ethyldiisopropylamine (0.525 ml, 3 mmol) in DMSO (1.5 ml) was stirredat 80° C. for 1.5 h. Isopropyl alcohol was added to the stirred solutionat the same temperature. The product started precipitating after theaddition of about 5 ml of isopropyl alcohol. Additional 1 ml ofisopropyl alcohol was added, the suspension was stirred at 80° C. for 5min and slowly cooled to room temperature. The product was filtered offafter overnight stirring at room temperature, washed with isopropylalcohol (2×) and dried on the filter. Yield: 640 mg.

Example 19 Procedure for the Preparation of Dasatinib Form A2

A mixture of compound 1 (5.91 g, 15 mmol), N-(2-hydroxyethyl)piperazine(3.91 g, 30 mmol) and N-ethyldiisopropylamine (5.25 ml, 30 mmol) in DMSO(15 ml) was stirred at 80° C. for 60 min. Isopropyl alcohol (46 ml) wasslowly added and the temperature was maintained at 80° C. The productstarted precipitating after 1-2 min. The suspension was stirred at 80°C. for 5 min and slowly cooled to room temperature. The product wasfiltered off after overnight stirring at room temperature, washed withisopropyl alcohol (2×15 ml) and dried on the filter. Yield: 6.18 g.

Example 20 Procedure for the Preparation of Dasatinib Form A1

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(390.6 mg, 3 mmol) and N-ethyldiisopropylamine (0.348 ml, 2 mmol) in DMF(1 ml) was stirred at 100° C. for 2.5 h. Isopropyl alcohol (10 ml) wasslowly added through a condenser and mild reflux was maintained for 10min. The suspension was cooled to room temperature. The product wasfiltered after 1 hour and washed with i-PrOH (3×) and dried on thefilter. Yield: 370 mg.

Example 21 Procedure for the Preparation of Dasatinib Form L2

A mixture of compound 1 (0.50 g, 1.27 mmol),N-(2-hydroxyethyl)piperazine (0.33 g, 2.54 mmol) andN-ethyldiisopropylamine (0.43 ml, 2.54 mmol) in DMSO (1.3 ml) wasstirred at 80-85° C. for 2 hours. Butan-2-ol (7 ml) was slowly added atthis temperature. The solution was slowly cooled to 0-5° C. The productwas filtered off, washed with butan-2-ol (10 ml) and dried on thefilter, than dried under reduced pressure at 40° C. for 6 hours. Yield:0.56 g.

Example 22 Procedure for the Preparation of Dasatinib Mixture of FormG+M

A mixture of compound 1 (394.3 mg, 1 mmol), N-(2-hydroxyethyl)piperazine(260.4 mg, 2 mmol) and N-ethyldiisopropylamine (0.35 ml, 2 mmol) inpyridine (2 ml) was stirred at 80° C. for 5 h. H₂O was added to thestirred solution at the same temperature. The product precipitated fromthe resulting solution after 5-7 min. The suspension was slowly cooledto room temperature. After 1 h the product was filtered off washed withH₂O (4×) and dried on the filter. Yield: 470 mg.

Example 23 Procedure for the Preparation of Dasatinib Form H1-7(Monohydrate)

A mixture of compound 1 (133.9 mg, 0.5 mmol),N-(2-hydroxyethyl)piperazine (260.4 mg, 2 mmol) andN-ethyldiisopropylamine (0.174 ml, 1 mmol) in DMF (0.5 ml) was stirredat 100° C. for 2.5 h. H₂O (3 ml) was added to the solution at the sametemperature. A gummy product precipitated. The suspension was allowed tocool slowly to room temperature and stirred for 2 h at room temperature.The product was filtered washed with H₂O (2×) and dried on the filter.Yield: 140 mg.

Example 24 Procedure for the Preparation of Dasatinib Form T1E2-1(Hemi-Ethanolate)

A mixture of compound 1 (591.4 mg, 1.5 mmol),N-(2-hydroxyethyl)piperazine (390.6 mg, 3 mmol) andN-ethyldiisopropylamine (0.525 ml, 3 mmol) in DMSO (1.5 ml) was stirredat 80° C. for 1.5 h. EtOH (10 ml) was added at the same temperature. Theresulting solution was slowly cooled. The product started precipitatingat 68° C. The mixture was cooled to room temperature. The product wasfiltered after 4 h, washed with EtOH (3×) and dried on the filter.Yield: 550 mg.

Example 25 Procedure for the Preparation of Dasatinib Form T1E2-1(Hemi-Ethanolate)

A mixture of compound 1 (0.45 g, 1.14 mmol),N-(2-hydroxyethyl)piperazine (0.30 g, 2.30 mmol) andN-ethyldiisopropylamine (0.30 ml, 1.75 mmol) in DMSO (5 ml) was stirredat 60-65° C. for 2 hours. EtOH (30 ml) was slowly added at thistemperature followed by H₂O (40 ml). The solution was slowly cooled to0-5° C. The product was filtered off and washed with ethanol (5 ml) anddried on the filter. Yield: 0.38 g.

Example 26 Procedure for the Preparation of Dasatinib AmorphousSubstance

A mixture of compound 1 (591.4 mg, 1.5 mmol),N-(2-hydroxyethyl)piperazine (390.6 mg, 3 mmol) andN-ethyldiisopropylamine (0.525 ml, 3 mmol) in DMF (1.5 ml) was stirredat 90° C. for 2.5 h. The solution was cooled down to 0° C. Than, water(20 ml) was added in to the mixture and the mixture was stirred for 1hour at 0° C. The product was filtered and washed with water (3×) anddried on the filter. Yield: 670 mg.

Example 27 Procedure for the Preparation of Dasatinib Form K1

A mixture of compound 1 (1.5 mmol), N-(2-hydroxyethyl)piperazine (3mmol) and N-ethyldiisopropylamine (3 mmol) in DMF was stirred at 100° C.for 4 h, n-propanol was added at this temperature. The suspension wasslowly cooled to 0-5° C. The product was filtered off, washed byi-propanol and dried on the filter.

Example 28 Procedure for the Preparation of Dasatinib Form K3

Dasatinib (form H1-7, 1 g) was dissolved in a mixture of n-PrOH (30 ml)and H₂O (5 ml) under reflux. The resulting solution was quickly cooledto 0-5° C. (ice bath). The product was filtered off after 1 h, washedwith n-PrOH and dried under reduced pressure at 50° C. for 2 h. Yield620 mg.

Example 29 Procedure for the Preparation of Dasatinib Form A1

A mixture of compound 1 (1.5 mmol), N-(2-hydroxyethyl)piperazine (3mmol) and N-ethyldiisopropylamine (3 mmol) in DMF was stirred at 100° C.for 4 h, i-propanol was added at this temperature. The suspension wasslowly cooled to 0-5° C. The product was filtered off, washed byi-propanol and dried on the filter.

Example 30 Procedure for the Preparation of Dasatinib Form A3

Dasatinib (form H1-7, 1 g) was dissolved in a mixture of iso-PrOH (30ml) and H₂O (14 ml) under reflux. The resulting solution was quicklycooled to 0-5° C. (ice bath). The product was filtered off after 1 h,washed with iso-PrOH and dried under reduced pressure at 50° C. for 2 h.Yield 620 mg.

Example 31 Procedure for the Preparation of Dasatinib Form A3

Dasatinib (form H1-7, 1 g) was dissolved in a mixture of iso-PrOH (30ml) and H2O (8 ml) under reflux. The resulting solution was quicklycooled to 0-5° C. (ice bath). The product was filtered off after 1 h,washed with iso-PrOH and dried under reduced pressure at 50° C. for 2 h.Yield 620 mg.

Example 32 Procedure for the Preparation of Dasatinib Form L1

A mixture of compound 1 (1.5 mmol), N-(2-hydroxyethyl)piperazine (3mmol) and N-ethyldiisopropylamine (3 mmol) in DMF was stirred at 100° C.for 4 h, 2-butanole was added at this temperature. The suspension wasslowly cooled to 0-5° C. The product was filtered off, washed by2-butanol and dried on the filter.

Example 33 Procedure for the Preparation of Dasatinib Form L3

Dasatinib (form L2, 1.0 g, 2.05 mmol) was suspended in 2-BuOH (30 ml)and heated to reflux. Water (2.0 ml) was slowly added at theseconditions to achieve complete dissolution. The resulting solution wasrefluxed 60 more minutes. The resulting solution was slowly cooled to0-5° C. The product was filtered off and dried on the filter. Yield:0.85 g, 85%.

Example 34 Procedure for the Preparation of Dasatinib Form N2

A mixture of compound 1 (1.5 mmol), N-(2-hydroxyethyl)piperazine (3mmol) and N-ethyldiisopropylamine (3 mmol) was heated in DMSO (1.3 ml)at 80-85° C. for 1.5 hours. n-Butanol (7.0 ml) was slowly added at thistemperature. The suspension was slowly cooled to 0-5° C. Product wasfiltered off and washed with n-butanol (10.0 ml) and dried on thefilter.

Example 35 Procedure for the Preparation of Dasatinib Form P

Dasatinib i-propanolate (form A3, 4.74 g) was dissolved in DMF (23.7 ml)at 100° C. After water (23.7 ml) was added at 100° C. The suspension wascooled to room temperature. The product was filtered off, washed withwater (3×) and dried on the filter.

Example 36 Procedure for the Preparation of Dasatinib Form Q

Dasatinib Form P was dried under flow of nitrogen at 70° C. for 2 hours.

Example 37 Procedure for the Preparation of Dasatinib Form AA

Dasatinib Form A21 (40 mg) [the detailed description has that these andall following methods were using Form C, please confirm that this shouldbe Form A21. Also please clarify whether the method could be practicedwith either form C or form A21.] was slurried in 1 ml MIPK and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AA. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C._The obtained sample was analyzed by XRD and found to be Form AA.

Example 38 Procedure for the Preparation of Dasatinib Form AB

Dasatinib Form A21 (40 mg) was slurried in 1 ml dimethoxyethane andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beForm AB.

Example 38a Procedure for the Preparation of Dasatinib Form AP

Dasatinib Form AB obtained by example 38 was dried in a bottle in aconventional oven overnight on 55° C._The obtained sample was analyzedby XRD and found to be Form AP.

Example 39 Procedure for the Preparation of Dasatinib Form AC

Dasatinib Form A21 (40 mg) was slurried in 1 ml cellosolve and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AC. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form AC.

Example 40 Procedure for the Preparation of Dasatinib Form AD

Dasatinib Form A21 (40 mg) was slurried in 1 ml methylacetate and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AD. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C._The obtained sample was analyzed by XRD and found to be Form AD.

Example 41 Procedure for the Preparation of Dasatinib Form AE

40 mg Dasatinib Form A21 was slurried in 1 ml MeOH and heated from 25 to65° C. with 0.1 deg/min heating rate till total dissolution. It wasmixed on 65° C. during 1 hour and cooled to 5° C. with 1 deg/min, thanfiltrated washed with 5 ml MeOH. Wet sample was obtained and analyzed byXRD and found to be Form AE. The wet sample was dried in a conventionaloven overnight on 55° C._The obtained sample was analyzed by XRD andfound to be Form AE.

Example 42 Procedure for the Preparation of Dasatinib Form AF

Dasatinib Form A21 (40 mg) was slurried in 1 ml ethylacetate and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AF. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form AF.

Example 43 Procedure for the Preparation of Dasatinib Form AG

Dasatinib Form A21 (40 mg) was slurried in 1 ml 2-pentanole and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AG. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form AG.

Example 44 Procedure for the Preparation of Dasatinib Form AI

Dasatinib Form A21 (40 mg) was slurried in 1 ml dimethyl carbonate andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beForm AI.

Example 44a Procedure for the Preparation of Dasatinib Form AY

Dasatinib Form AI obtained by example 44 was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form AY.

Example 45 Procedure for the Preparation of Dasatinib Form AJ

Dasatinib Form A21 (40 mg) was slurried in 1 ml isopropylacetate andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beForm AJ. The wet sample was analyzed by PXRD providing the followingcharacteristics peaks at about 5.8, 10.2, 11.5, 12.7, 17.4 and 22.0±0.2degrees 2-theta and a PXRD pattern depicted in FIG. 107. The wet samplewas dried in a bottle in a conventional oven overnight on 55° C. Theobtained sample was analyzed by PXRD and found to be Form AJ.

Example 46 Procedure for the Preparation of Dasatinib Form AK

Dasatinib Form A21 (40 mg) was slurried in 1 ml ethyleneglycol andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beForm AK.

Example 46a Procedure for the Preparation of Dasatinib Form AW

Dasatinib Form AK obtained by example 46 was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form AW.

Example 47 Procedure for the Preparation of Dasatinib Form AL

Dasatinib Form A21 (40 mg) was slurried in dichloromethane and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 30° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AL. Thewet sample was analyzed by PXRD providing the following characteristicspeaks at about 5.9, 12.3, 17.8, 18.4, 18.7, 23.0 and 23.8±0.2 degrees2-theta, and a PXRD pattern depicted in FIG. 108. The wet sample wasdried in a bottle in a conventional oven overnight on 55° C. Theobtained sample was analyzed by XRD and found to be Form AL.

Example 48 Procedure for the Preparation of Dasatinib Form AM

Dasatinib Form A21 (40 mg) was slurried in 1 ml methylformate and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 30° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AM. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form AM.

Example 49 Procedure for the Preparation of Dasatinib Form AN

Dasatinib Form A21 (40 mg) was slurried in 1 ml tert-butanol and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AN. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form AN.

Example 50 Procedure for the Preparation of Dasatinib Amorphous

Dasatinib Form A21 (40 mg) was slurried in 1 ml 1,2-dichlorobenzene andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beAmorphous Form.

Example 50a Procedure for the Preparation of Dasatinib Form BA

Dasatinib amorphous obtained by example 50 was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form BA.

Example 51 Procedure for the Preparation of Dasatinib Form K3

Dasatinib Form A21 (40 mg) was slurried in 1 ml n-propanol and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form K3. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form K3.

Example 52 Procedure for the Preparation of Dasatinib Form AE

Dasatinib Form A21 (40 mg) was dissolved in 200 μl DMSO and heated from25° C. till 65° C. with 0.05° C./min heating rate. The sample with thesolvent was mixed at 65° C. and 800 μl MeOH was injected into thesystem. Then it was cooled down to 5° C. with 1° C./min heating rate.The suspension was filtered and washed with ˜5 ml MeOH. Wet sample wasobtained and analyzed by XRD and found to be Form AE.

Example 53 Procedure for the Preparation of Dasatinib Form AE

40 mg Dasatinib Form A21 was slurried in 1 ml MeOH and heated from 25 to65° C. with 0.1 deg/min heating rate till total dissolution. It wasmixed on 65° C. during 1 hour and cooled to 5° C. with 0.1 deg/min, thenfiltrated washed with 5 ml MeOH. Wet sample was obtained and analyzed byXRD and found to be Form AE.

Example 54 Procedure for the Preparation of Dasatinib Form AE

40 mg Dasatinib Form A21 was dissolved in 200 μl DMSO and slurried on25. On 25° C. 800 μl MeOH was injected into the system, than spontaneouscrystallization was observed. The obtained crystals were filtrated andwashed with ˜5 ml MeOH. Wet sample was obtained and analyzed by XRD andfound to be Form AE.

Example 55 Procedure for the Preparation of Dasatinib Form AH

Dasatinib Form A21 (40 mg) was slurried in 1 ml tert-butanol and heatedfrom 25° C. till 50° C. with 0.5° C./min heating rate. The sample withthe solvent was slurried at 50° C. for 6 hours, cooled to 25° C. with0.5° C./min cooling rate, slurried overnight at 25° C. The sample waskept in a hood at atmospheric pressure and room temperature overnight.Wet sample was obtained and analyzed by XRD and found to be Form AH. Thewet sample was dried in a bottle in a conventional oven overnight on 55°C. The obtained sample was analyzed by XRD and found to be Form AH.

Example 56 Procedure for the Preparation of Dasatinib Amorphous

Dasatinib Form A21 (40 mg) was slurried in 1 ml benzyl alcohol andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beAmorphous Form.

Example 57 Procedure for the Preparation of Dasatinib Form AQ

Dasatinib Form A21 (40 mg) was slurried in 1 ml methylethylketone

(“MEK”) and heated from 25° C. till 50° C. with 0.5° C./min heatingrate. The sample with the solvent was slurried at 50° C. for 6 hours,cooled to 25° C. with 0.5° C./min cooling rate, slurried overnight at25° C. The sample was kept in a hood at atmospheric pressure and roomtemperature overnight. Wet sample was obtained and analyzed by XRD andfound to be Form AQ. The wet sample was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form AQ.

Example 58 Procedure for the Preparation of Dasatinib Form AR

Dasatinib Form A21 (40 mg) was slurried in 1 ml monochlorobenzene andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beForm AR.

Example 58a Procedure for the Preparation of Dasatinib Form BB

Dasatinib form AR obtained by example 58 was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form BB.

Example 59 Procedure for the Preparation of Dasatinib Form AS

Dasatinib Form A21 (40 mg) was slurried in 1 ml propylene glycolmonoethyl ether (“PGME”) and heated from 25° C. till 50° C. with 0.5°C./min heating rate. The sample with the solvent was slurried at 50° C.for 6 hours, cooled to 25° C. with 0.5° C./min cooling rate, slurriedovernight at 25° C. The sample was kept in a hood at atmosphericpressure and room temperature overnight. Wet sample was obtained andanalyzed by XRD and found to be Form AS. The wet sample was dried in abottle in a conventional oven overnight on 55° C. The obtained samplewas analyzed by XRD and found to be Form AS.

Example 60 Procedure for the Preparation of Dasatinib Amorphous

Dasatinib Form A21 (40 mg) was slurried in 1 ml propylene glycol andheated from 25° C. till 50° C. with 0.5° C./min heating rate. The samplewith the solvent was slurried at 50° C. for 6 hours, cooled to 25° C.with 0.5° C./min cooling rate, slurried overnight at 25° C. The samplewas kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beAmorphous Form.

Example 61 Procedure for the Preparation of Dasatinib Form AT

Dasatinib Form A21 (40 mg) was slurried in 1 ml glycerol and heated from25° C. till 50° C. with 0.5° C./min heating rate. The sample with thesolvent was slurried at 50° C. for 6 hours, cooled to 25° C. with 0.5°C./min cooling rate, slurried overnight at 25° C. The sample was kept ina hood at atmospheric pressure and room temperature overnight. Wetsample was obtained and analyzed by XRD and found to be Form AT.

Example 61a Procedure for the Preparation of Dasatinib Form BC

Dasatinib form AT obtained by example 61 was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form BC.

Example 62 Procedure for the Preparation of Dasatinib Form AU

Dasatinib Form A21 (40 mg) was slurried in 1 ml cyclopentyl methyl etherand heated from 25° C. till 50° C. with 0.5° C./min heating rate. Thesample with the solvent was slurried at 50° C. for 6 hours, cooled to25° C. with 0.5° C./min cooling rate, slurried overnight at 25° C. Thesample was kept in a hood at atmospheric pressure and room temperatureovernight. Wet sample was obtained and analyzed by XRD and found to beForm AU. The wet sample was dried in a bottle in a conventional ovenovernight on 55° C. The obtained sample was analyzed by XRD and found tobe Form AU.

Example 63 Procedure for the Preparation of Dasatinib Form AV

Dasatinib Form A21 (40 mg) was slurried in 1 ml methyl tert butyl ether(“MTBE”) and heated from 25° C. till 50° C. with 0.5° C./min heatingrate. The sample with the solvent was slurried at 50° C. for 6 hours,cooled to 25° C. with 0.5° C./min cooling rate, slurried overnight at25° C. The sample was kept in a hood at atmospheric pressure and roomtemperature overnight. Wet sample was obtained and analyzed by XRD andfound to be Form AV. The wet sample was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form AV.

Example 64 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

Dasatinib Form K2 (solvate of n-propanol and DMSO) (500 mg) was stirredin 10 ml EtOH at r.t. for 4 h.

Example 65 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

Dasatinib Form K2 (solvate of n-propanolate and DMSO) (500 mg) wasrefluxed in 10 ml EtOH for 4 h.

Example 66 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

Dasatinib Form A2, (solvate of i-propanolate and DMSO) solvate (500 mg)was stirred in 10 ml EtOH at r.t. for 4 h.

Example 67 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

Dasatinib 2-butanolate (form L2, 1.0 g, 2.05 mmol) was suspended in EtOH(8.1 ml). After heating at 80° C. was added next portion EtOH (4.0 ml).Then water was added (2.05 ml) to achieve complete dissolution. Thesolution was cooled to 0-5° C. The product was filtered off and dried onthe filter. Yield: 0.50 g, 71.4%.

EtOH—W (6:1).

Example 68 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

Dasatinib n-propanolate (form K2, 0.60 g, 1.23 mmol) was suspended inEtOH (7.0 ml). After heating at 80° C. was added next portion EtOH (3.4ml). Then water was added (1.8 ml) to achieve complete dissolution. Thesolution was cooled to 0-5° C. The product was filtered off and dried onthe filter. Yield: 0.43 g, 71.7%.

EtOH—W (6:1)

Example 69 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

Dasatinib n-butanolate (form BU-2, 1.0 g) was refluxed in EtOH (22 ml).After water (3 ml) was added at these conditions to achieve completedissolution. To the solution was added dasatinib anhydrous (50 mg) at68° C. The suspension was slowly cooled to room temperature. The productwas filtered off and dried on the filter.

Example 70 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

40 mg DAS (Form A21)+880 μl EtOH+120 μl water heating 25-75° C. with 0.1deg/min, slurry on 75° C. during 1 hour, cooling till 5° C. with 1deg/min, filtration, washing with ˜5 ml EtOH, than XRD.

Example 71 Procedure for the Preparation of Pure Dasatinib Form T1E2-1(Hemi-Ethanolate)

40 mg DAS (Form A21)+880 μl EtOH+120 μl water heating 25-65° C. with0.05 deg/min, slurry on 65° C. during 1 hour, injection of 320 μl watercooling till 5° C. with 1 deg/min, washing with ˜5 ml EtOH, than XRD.

Example 72 Procedure for the Preparation of Dasatinib Form A3

Dasatinib (form A3, 3.50 g) was dissolved in a mixture of i-PrOH—H2O30:8 (in 140 ml) under reflux. The solution was slowly cooled to about70° C. The product started to crystallized at 65-70° C. Temperature waskept at this value for about 20 min then it was decreased to 50° C. andkept for 15 min. The mixture was slowly cooled to room temperature andstirred at room temperature for 1 h. The product was filtered off,washed with i-PrOH (2×) and dried under reduced pressure at 50° C. for 3h. Yield: 2.44 g.

Example 73 Procedure for the Preparation of Crude Dasatinib form A21 in1-g Scale

A mixture of compound 1 (1.58 g, 4 mmol) andN-(2-hydroxyethyl)piperazine (1.56 g, 12 mmol) was stirred in DMSO (4ml) at 70° C. for 3 h. i-PrOH (12 ml) was added at the same temperatureto precipitate the product. The mixture was cooled to room temperatureduring 30 min and stirred at room temperature for 1 h. The product wasfiltered, washed with i-PrOH (2×) and dried. Yield: 1.37 g, 70%.

Example 74 Procedure for the Preparation of Dasatinib Form A3 in 1-gScale

Crude Dasatinib (form A21, 800 mg, example 73) was dissolved in amixture of i-PrOH—H₂O 30:8 (32 ml) under reflux. The solution was slowlycooled to about 70° C. The product started to crystallize at 65-70° C.Temperature was kept at this value for about 20 min then it wasdecreased to 50° C. and kept for 15 min. The mixture was slowly cooledto room temperature and stirred at room temperature for 1 h. The productwas filtered off, washed with i-PrOH (2×) and dried under reducedpressure at 50° C. for 3 h. Yield: 580 mg, 73%.

Example 75 Procedure for the preparation of crude Dasatinib form A21 in1-kg scale

A mixture of compound 1 (1000 g, 2.54 mol) andN-(2-hydroxyethyl)piperazine (991 g, 7.61 mol) was stirred in DMSO (2.54l) under nitrogen at 70° C. for 3 h. i-PrOH (7.62 l) was added at thesame temperature during 15 min to precipitate the product. The mixturewas cooled to 20° C. during 30 min and stirred at 20° C. for 1 h. Theproduct was filtered, washed with i-PrOH (2×3.5 l) and dried. Yield: 866g, 70%.

Example 76 Procedure for the preparation of Dasatinib Form A3 in 1-kgscale

Crude Dasatinib (form A21, 800 g, example 75) was dissolved in a mixtureof i-PrOH—H₂O 30:8 (32 l) under reflux under nitrogen. The solution wascooled to about 70° C. The product started to crystallize at 65-70° C.Temperature was kept at this value for about 20 min then it wasdecreased to 50° C. and kept for 15 min. The mixture was slowly cooledto room temperature and stirred at room temperature for 1 h. The productwas filtered off, washed with i-PrOH (2×3 l) and dried under reducedpressure at 50° C. for 3 h. Yield: 580 g, 73%.

Example 77 Procedure for the preparation of Dasatinib Form BD

40 mg DAS (Form A21)+1 ml DiMeCarbonate heating till 50° C. with 0.5°C./min heating rate, slurry on 50° C. during 4 hours, cooling to 25° C.with 0.1° C./min cooling rate, slurry during 3 days on 25° C. andevaporation of the solvent in the hood during 2 days. Then drying inoven on 55° C. overnight.

Example 78 Procedure for the preparation of Dasatinib Form BG

40 mg DAS (Form A21)+1 ml MIPK heating till 50° C. with 0.5° C./minheating rate, slurry on 50° C. during 4 hours, cooling to 25° C. with0.1° C./min cooling rate, slurry during 3 days on 25° C. and evaporationof the solvent in the hood during 2 days, then drying in oven on 55° C.overnight.

Example 79 Procedure for the preparation of Dasatinib Form BJ

40 mg DAS (Form A21)+1 ml monochlorobenzene heating till 50° C. with0.5° C./min heating rate, slurry on 50° C. during 4 hours, cooling to25° C. with 0.1° C./min cooling rate, slurry during 3 days on 25° C. andevaporation of the solvent in the hood during 2 days.

Example 79a Procedure for the preparation of Dasatinib Form BB

Dasatinib form BJ obtained by example 79 was dried in a bottle in aconventional oven overnight on 55° C. The obtained sample was analyzedby XRD and found to be Form BB.

Example 80 Preparation of a pharmaceutical formulation of Dasatinib formA3

Dasatinib form A3, having the main PXRD peaks at 6.0, 11.9, 12.0, 14.9,17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees two-theta, andall the components presented in the below table were weighed togetherand blended.

Component Weight (mg) Dasatinib Form A3 70 Lactose monohydrate 100Magnesium stearate 5 Microcrystalline celulose 50 Hydroxypropylmethylcelulose 50 Total weight 275

The above blend was pressed in order to form a tablet which was thenanalyzed by PXRD providing the following main PXRD peaks: 6.0, 11.9,14.9, 17.9, 18.3, 24.2 and 24.7±0.2 belonging to form A3.

Example 81 Procedure for the preparation of Dasatinib Form B

Dasatinib Form C (1 g) and 25 ml of methanol were mixed and the blendwas gradually heated up to 65° C. during 1 hour. The obtained opalescentsolution was kept at 65° C. for 1 hour. Then the solution was graduallycooled down to 5° C. during 1 hour. The product was filtered off, washedwith methanol and dried at 55° C. overnight.

Example 82 Preparation of a Pharmaceutical Formulation of DasatinibAmorphous

Dasatinib amorphous and all the components presented in the below tableare weighed together and blended.

Component Weight (mg) Dasatinib amorphous 70 Lactose monohydrate 100Magnesium stearate 5 Microcrystalline celulose 50 Hydroxypropylmethylcelulose 50 Total weight 275

The above blend is pressed in order to form a tablet which is thenanalyzed by PXRD to provide amorphous phase with peaks of excipients.

Example 83 Preparation of a Pharmaceutical Formulation of Dasatinib FormB

Dasatinib form B, having the main PXRD peaks at 7.2, 11.9, 14.4, 16.5,17.3, 19.1, 20.8, 22.4, 23.8, 25.3 and 29.1±0.2 degrees two-theta, andall the components presented in the below table were weighed togetherand blended.

Component Weight (mg) Dasatinib Form B 70 Lactose monohydrate 100Magnesium stearate 5 Microcrystalline celulose 50 Hydroxypropylmethylcelulose 50 Total weight 275

The above blend was pressed in order to form a tablet which was thenanalyzed by PXRD providing main PXRD peaks 7.2 and 14.4 degreestwo-theta.

Example 84 Preparation of a Pharmaceutical Formulation of Dasatinib FormC

Dasatinib form C having the main PXRD peaks at 6.1, 11.8, 15.1, 16.6,18.2, 19.3, 20.8, 21.6, 23.0, 23.8, 24.3, 24.8 and 25.5±0.2 degrees2-theta, and all the components presented in the below table are weighedtogether and blended.

Component Weight (mg) Dasatinib Form C 70 Lactose monohydrate 100Magnesium stearate 5 Microcrystalline celulose 50 Hydroxypropylmethylcelulose 50 Total weight 275

The above blend is pressed in order to form a tablet which is thenanalyzed by PXRD to provide main PXRD peaks 6.1, 11.8, 15.1, 18.2 and24.3 degrees two-theta.

Example 85 Preparation of a pharmaceutical formulation of Dasatinib formA21

Dasatinib form A21 having the main PXRD peaks at 6.0, 11.9, 15.1, 18.2,20.8, 23.9, 24.3 and 25.5±0.2 degrees 2-theta, and all the componentspresented in the below table were weighed together and blended.

Component Weight (mg) Dasatinib Form A21 70 Lactose monohydrate 100Magnesium stearate 5 Microcrystalline celulose 50 Hydroxypropylmethylcelulose 50 Total weight 275

The above blend was pressed in order to form a tablet which was thenanalyzed by PXRD providing main PXRD peaks 6.0, 11.9, 15.1, 18.2 and24.3 degrees two-theta.

Example 86 Procedure for the preparation of Dasatinib Form BL

Crude dasatinib form A21(240 mg) was dissolved in glycerol formal (1.25ml) by heating to 130° C. for 1 min. The solution was allowed to coolspontaneously to 20° C. within about 20 min and than the sample wasallowed to stand at 20° C. for additional 20 min. Crystals formed wererecovered by filtration, washed by TBME (15 ml) and dried on air for 1h.

Example 87 Procedure for the preparation of Dasatinib Form N-6

Dasatinib (form P) was dried at 200° C. under nitrogen for 2 hours.

Example 88 Procedure for the preparation of Dasatinib Form N-6

Dasatinib (200 mg, form A3) was heated on oil bath gradually up to 208°C. at final 0.7 Pa for about 15 min. None sublimation was observed. MSproved that the sample was pure dasatinib (without any chemical change).

Example 89 Procedure for the preparation of Dasatinib Form BM

Suspension 30 mg of Dasatinib (form C) in MeOH (1 ml) was dissolved byheating at 64° C. for 30 minutes and then the temperature was slasheddown to 0° C. during 1-2 minutes. Crystalline phase was createdimmediately after the temperature drop-off. The solid was separated byfiltration and dried up on filter under stream of N2.

Example 90 Procedure for the preparation of Dasatinib Form BM

Suspension 40 mg Dasatinib (form C) at 1 ml MeOH was cooled from R.T. to(−15° C.) during 5 min. Then heating to 65° C. during 170 min., 10 min.keeping 65° C. and then cooling to (−15° C.) during 170 min. Filtrationunder N2.

Example 91 Conversion of form N6 to form B

Dasatinib (form N-6, 75 mg) was put into vial and 1 ml of methanol wasadded. The slurry was then left at 0° C. for 2 days. The solid phase wasfiltered off and left to dry on air. The sample was analyzed by PXRD andprovided form N-6 containing about 10% of form B.

Example 92 Conversion of form N6 to form B

Dasatinib (form N-6, 75 mg) was put into vial and 1 ml of methanol wasadded. The slurry was then left at 20° C. for 2 days respectively. Thesolid phase was filtered off and left to dry on air. The sample wasanalyzed by PXRD and provided form N-6 containing about 1% of form B.

1. An isopropyl alcohol solvate of dasatinib characterized by dataselected from a group consisting of: a powder x-ray diffraction patternhaving any three peaks selected from the group consisting of: 6.0, 11.9,12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees2-theta, a powder x-ray diffraction pattern as depicted in FIG. 18, asolid-state ¹³C NMR spectrum having signals at 139.2 and 127.6±0.2 ppm;a solid-state ¹³C NMR spectrum having chemical shift differences betweenthe signal exhibiting the lowest chemical shift and another in thechemical shift range of 100 to 180 ppm of 14.2 and 2.6±0.1 ppm; and aunit cell with the following parameters as determined by crystalstructure determination using synchrotron powder diffraction data: Celldimensions Cell length a 14.9942(5) Å Cell length b 8.45434(22) Å Celllength c 22.6228(16) Å Cell angle alpha 90.0° Cell angle beta 95.890(4)°Cell angle gamma 90.0° Cell volume 2852.67(21) Å³ Symmetry cell settingmonoclinic Symmetry space group name P 2₁/c

a powder x-ray diffraction pattern and calculated powder x-raydiffraction pattern as depicted in FIG. 96, and combinations thereof. 2.The isopropyl alcohol solvate of dasatinib of claim 1, characterized bythe powder x-ray diffraction pattern having any three peaks selectedfrom the group consisting of: 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8,21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta.
 3. The isopropyl alcoholsolvate of dasatinib of claim 1, characterized by a powder x-raydiffraction pattern as depicted in FIG.
 18. 4. The isopropyl alcoholsolvate of dasatinib of claim 1, characterized by a solid-state ¹³C NMRspectrum having signals at 139.2 and 127.6±0.2 ppm.
 5. The isopropylalcohol solvate of dasatinib of claim 1, characterized by a solid-state¹³C NMR spectrum having chemical shift differences between the signalexhibiting the lowest chemical shift and another in the chemical shiftrange of 100 to 180 ppm of 14.2 and 2.6±0.1 ppm.
 6. The isopropylalcohol solvate of dasatinib of claim 2, characterized by a powder x-raydiffraction pattern having any five peaks selected from the groupconsisting of 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2and 24.7±0.2 degrees 2-theta.
 7. The isopropyl alcohol solvate ofdasatinib of claim 2, characterized by a powder x-ray diffractionpattern having peaks at 6.0 and 17.9±0.2 degrees 2-theta and any threepeaks at positions selected from the group consisting of: 11.9, 14.9,21.4, 24.2 and 24.7±0.2 degrees 2-theta.
 8. The isopropyl alcoholsolvate of dasatinib of claim 2, further characterized by data selectedfrom the group consisting of: a powder x-ray diffraction pattern withpeaks at 6.0, 11.9, 12.0, 14.9, 17.9 and 18.3±0.2 degrees 2-theta and apowder x-ray diffraction pattern with peaks at 11.9, 12.0, 21.4, 22.9and 24.7±0.2 degrees 2-theta.
 9. The isopropyl alcohol solvate ofdasatinib of claim 1, further characterized by a content of isopropylalcohol of about 9% to about 13% by weight.
 10. The isopropyl alcoholsolvate of dasatinib of claim 1, having less than about 15% by weight ofcrystalline dasatinib forms: N-6 characterized by a powder x-raydiffraction pattern having peaks at 6.9, 12.4, 13.2, 13.8, 16.8, 17.2,21.1, 24.4, 24.9 and 27.8±0.2 degrees 2-theta, and H1-7 characterized bya powder x-ray diffraction pattern having peaks at 4.6, 9.2, 11.2, 13.8,15.2, 17.9, 19.5, 23.1, 23.6, 25.9 and 28.0±0.2 degrees 2-theta.
 11. Aformulation comprising the isopropyl alcohol solvate of dasatinib ofclaim 1 and at least one pharmaceutically acceptable excipient.
 12. Apharmaceutical composition comprising the isopropyl alcohol solvate ofdasatinib according to claim 1, and at least one pharmaceuticallyacceptable excipient.
 13. A method for preparing an isopropyl alcoholsolvate of dasatinib characterized by data selected from a groupconsisting of: a powder x-ray diffraction pattern having any three peaksselected from the group consisting of: 6.0, 11.9, 12.0, 14.9, 17.9,18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta, a powderx-ray diffraction pattern as depicted in FIG. 18, a solid-state ¹³C NMRspectrum having signals at 139.2 and 127.6±0.2 ppm; a solid-state ¹³CNMR spectrum having chemical shift differences between the signalexhibiting the lowest chemical shift and another in the chemical shiftrange of 100 to 180 ppm of 14.2 and 2.6±0.1 ppm; and a unit cell withthe following parameters as determined by crystal structuredetermination using synchrotron powder diffraction data: Celldimensions: Cell length a 14.9942(5) Å Cell length b 8.45434(22) Å Celllength c 22.6228(16) Å Cell angle alpha 90.0° Cell angle beta 95.890(4)°Cell angle gamma 90.0° Cell volume 2852.67(21) Å³ Symmetry cell settingmonoclinic Symmetry space group name P 2₁/c

a powder x-ray diffraction pattern and calculated powder x-raydiffraction pattern as depicted in FIG. 96, and combinations thereof,said method comprising crystallizing dasatinib from a mixture ofisopropyl alcohol and water.
 14. The method of claim 13, wherein thecrystallization comprises providing a solution of dasatinib in a mixtureof isopropyl alcohol and water, and precipitating the isopropyl alcoholsolvate of dasatinib to obtain a suspension.
 15. The method of claim 14,wherein the solution is provided by combining dasatinib, isopropylalcohol and water, and heating the combination.
 16. The method of claim15, wherein the heating is to about reflux temperature.
 17. The methodof claim 14, wherein the precipitation is performed by cooling thesolution
 18. The method of claim 17, wherein the cooling is to atemperature of about 20° C. to about 0° C.
 19. The method of claim 13,further comprising recovering the isopropyl alcohol solvate of dasatinib20. A process for preparing a pharmaceutical composition comprisingcombining the dasatinib of claim 1, and at least one pharmaceuticallyacceptable excipient.